Re: 맞춤의학 chronotherapy 암의 발생과 치료.. 암세포 주기에 따른 치료법!!

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맞춤의학의 끝판왕은 일주기리듬에 있는 듯...

중추적 생체시계 조절기인 중추 생체시계 조절기—상시교차핵(SCN)—의 리듬에 맞추기 위해 신체는

분자적, 세포적, 체계적 피드백 루프의 다층적 시스템을 통해 수면-각성 주기, 호르몬 리듬, 대사 과정을 조정.

1. 주 시계: 상시교차핵(SCN)

• SCN은 뇌의 전방 시상하부에 위치하며 포유류의 중앙 생체시계
• SCN은 내재적 광감각 망막 신경절 세포(ipRGC)를 통해 광 입력을 받으며, 이 세포는 멜라놉신을 발현
• SCN 신경세포는 핵심 시계 유전자(예: BMAL1, CLOCK, PER1-3, CRY1-2)를 발현하며 자율적 24시간 진동을 생성

멜라놉신(melanopsin)은 **망막의 내재적 광감수신경절 세포(intrinsically photosensitive retinal ganglion cells, ipRGCs)**에 발현되는 광감각 색소로, **일주기리듬(circadian rhythm)**을 조절하는 **상시교차핵(suprachiasmatic nucleus, SCN)**을 자극하는 데 핵심적인 역할을 합니다. 이 과정의 기전은 다음과 같은 단계로 설명됩니다:

1. 멜라놉신의 광감작 메커니즘
빛 감지:
멜라놉신은 **480 nm 파장(청색광)**에 최대 감수성을 가지며, 빛에 노출되면 Gq 단백질 경로를 활성화합니다.

신호 전달:
멜라놉신 활성화 → Gq 단백질 → 포스포리파제 C(PLC) → IP3 생성 → 세포 내 칼슘(Ca²⁺) 농도 증가 → TRP 채널 개방.

전위 변화:
칼슘 유입으로 인해 **탈분극(depolarization)**이 발생하며, 이는 **액션 포텐셜(action potential)**을 유발합니다.

2. SCN으로의 신호 전달 경로
망막-하측시신경로(retinohypothalamic tract, RHT):
ipRGCs의 축삭은 **시신경(optic nerve)**을 통해 직접 **상시교차핵(SCN)**으로 신호를 전달합니다.

신경전달물질:
주로 **글루탐산(glutamate)**과 **펩타이드(PACAP)**를 분비합니다.

SCN의 빛 동기화:
SCN은 빛 신호를 받아 **일주기리듬 조절 유전자(Clock, Bmal1, Per, Cry)**의 발현을 조절합니다.

유전자 발현 리듬:
빛 → Per/Cry 유전자 발현 ↑ → 핵심 시계 유전자 네트워크 조정 → 24시간 주기 유지.

3. 생체시계의 조절 과정
빛 입력:
아침 빛 → ipRGCs 활성화 → SCN에 신호 전달.

SCN의 반응:

멜라토닌 억제: 빛 노출 시 SCN이 **송과체(pineal gland)**를 통해 멜라토닌 분비 ↓.

체온 및 호르몬 조절: SCN이 시상하부-뇌하수체 축을 통해 코르티솔, 성장호르몬 등 조절.

주변 조직 동기화:
SCN은 자율신경계와 호르몬을 통해 간, 근육 등 말초 조직의 생체시계를 조정합니다.

4. 임상적 의미
수면 장애:
청색광(스마트폰, LED) 과노출 → 멜라놉신 과활성화 → SCN 리듬 혼란 → 수면주기 장애(insomnia).

계절성 우울증(SAD):
겨울철 빛 부족 → SCN 기능 저하 → 멜라토닌 분비 이상 → 기분 장애.

항암 치료:
일주기리듬을 고려한 시간 요법(chronotherapy) 개발 가능성.

5. 최신 연구 동향
멜라놉신 유전자 조작:
빛 감수성 조절을 통한 수면 장애 치료 연구 진행 중.

인공 빛 노출 최적화:
청색광 필터링이 SCN 동기화에 미치는 영향 분석.

멜라놉신-SCN 축은 빛-생체시계 연결의 핵심이며, 이를 이해하면 수면, 대사, 정신건강 관리에 새로운 전략을 제시할 수 있습니다.

2. 수면-각성 주기 조절🧬 분자적 기반

• BMAL1/CLOCK 이량체는 PER와 CRY의 전사 활성을 활성화하며, 이후 이 유전자들은 BMAL1/CLOCK 활성을 억제함으로써 자신의 전사를 억제합니다—이 과정을 전사-번역 피드백 루프(TTFL)라고 합니다.
• 이 분자적 리듬은 SCN 내 신경 세포의 흥분성을 조절하며, 이는 수면 조절 중추로 신호를 전달합니다.

신경 출력

• SCN은 다음과 같이 투사됩니다:

🧪 신경조절물질

• 멜라토닌 (SCN의 교감신경 경로를 통해 어둠에 반응하여 송과체에서 분비됨)은 수면을 촉진합니다.
• 코르티솔 (각성 촉진 호르몬)은 SCN에 의해 조절되는 시상하부-뇌하수체-부신 (HPA) 축의 조절로 인해 아침 초기에 정점을 이룹니다.

3. 호르몬 주기 조절A. 멜라토닌 (수면 관련)

• SCN → PVN → IML → 상경부 신경절 → 송과체
• 빛은 이 경로를 억제하며, 어둠은 억제를 해제하여 멜라토닌 분비를 촉진
• 멜라토닌은 SCN의 MT1/MT2 수용체에 피드백을 주어 생체 리듬 단계를 강화

B. 코르티솔 (각성 관련)

• SCN은 간접적으로 CRH (코르티코트로핀 방출 호르몬) 분비를 자극 → ACTH → 코르티솔
• 코르티솔 분비는 일일 리듬을 보이며, 아침에 정점을 이루고 저녁에 억제

C. 생식 호르몬

• LH, FSH는 뇌하수체에서 분비되며, SCN으로부터 간접적인 입력을 받는 GnRH 신경세포를 통해 생체 리듬에 의해 영향.

4. 대사 사이클 조절A. 주변 시계

• 간, 근육, 지방, 췌장 등은 SCN과 유사한 TTFL에 의해 구동되는 자체 생체시계를 가지고 있음.
• 그러나 식사, 활동, 온도 변화 등으로 인해 SCN과 비동기화될 수 있습니다.

B. 식사-금식 주기

• SCN은 식사 행동 조절을 통해 간접적으로 대사 주기를 조절하며, 이는 주변 시계를 동기화합니다.
• 영양소 센서 (예: AMPK, SIRT1, NAD+ 수준)는 세포 에너지 상태를 시계 유전자 조절과 연결합니다.

C. 대사 조절 호르몬

• 인슐린은 식사 리듬을 따릅니다
• 글루카곤과 레프틴/그렐린도 일주기 변동을 보입니다
• PPARs, REVERBs, 및 RORs는 영양소 신호와 시계 유전자 발현을 통합합니다

5. 동기화 및 동기화

• Zeitgebers(“시간 제공자”)인 빛, 음식, 신체 활동 및 온도는 SCN과 주변 시계를 동기화합니다
• SCN은 하류 시계를 다음과 통해 동기화합니다:

Discov Oncol

. 2024 Dec 18;15:767. doi: 10.1007/s12672-024-01643-4

Circadian rhythms and cancer: implications for timing in therapy

Mohamed El-Tanani 1,2,✉, Syed Arman Rabbani 1,2, Areeg Anwer Ali 1,2, Ibrahim Ghaleb Ali Alfaouri 2,3, Hamdi Al Nsairat 4, Israa Hamid Al-Ani 4, Alaa A Aljabali 5, Manfredi Rizzo 6, Dimitrios Patoulias 7,8, Mohammad Ahmed Khan 9, Suhel Parvez 10, Yahia El-Tanani 11

• Author information
• Article notes
• Copyright and License information

PMCID: PMC11655929  PMID: 39692981

Abstract

Circadian rhythms, intrinsic cycles spanning approximately 24 h, regulate numerous physiological processes, including sleep–wake cycles, hormone release, and metabolism. These rhythms are orchestrated by the circadian clock, primarily located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruptions in circadian rhythms, whether due to genetic mutations, environmental factors, or lifestyle choices, can significantly impact health, contributing to disorders such as sleep disturbances, metabolic syndrome, and cardiovascular diseases. Additionally, there is a profound link between the disruption of circadian rhythms and development of various cancer, the influence on disease incidence and progression. This incurred regulation by circadian clock on pathways has its implication in tumorigenesis, such as cell cycle control, DNA damage response, apoptosis, and metabolism. Furthermore, the circadian timing system modulates the efficacy and toxicity of cancer treatments. In cancer treatment, the use of chronotherapy to optimize the timing of medical treatments, involves administering chemotherapy, radiation, or other therapeutic interventions at specific intervals to enhance efficacy and minimize side effects. This approach capitalizes on the circadian variations in cellular processes, including DNA repair, cell cycle progression, and drug metabolism. Preclinical and clinical studies have demonstrated that chronotherapy can significantly improve the therapeutic index of chemotherapeutic agents like cisplatin and 5-fluorouracil by enhancing anticancer activity and reducing toxicity. Further research is needed to elucidate the mechanisms underlying circadian regulation of cancer and to develop robust chronotherapeutic protocols tailored to individual patients’ circadian profiles, potentially transforming cancer care into more effective and personalized treatment strategies.

초록

생체 리듬은 약 24시간 주기로 반복되는 내재적 주기로,

수면-각성 주기,

호르몬 분비,

대사 등 다양한 생리적 과정을 조절합니다.

physiological processes, including

sleep–wake cycles,

hormone release, and

metabolism.

이러한 리듬은

주로 뇌의 시상하부 내 상시교차핵(SCN)에 위치한

생체 시계에 의해 조절됩니다.

생체 리듬의 교란은

유전적 변이,

환경적 요인,

생활 방식의 선택 등 다양한 원인으로 발생할 수 있으며,

이는 건강에 심각한 영향을 미쳐

수면 장애, 대사 증후군, 심혈관 질환 등 다양한 질환의 발생에 기여합니다.

또한

생체 리듬의 교란과 암의 발생 및 진행 사이에는 깊은 연관성이 있으며,

이는 질병의 발생률과 진행에 영향을 미칩니다.

생체시계가 조절하는 경로는

종양 발생에 중요한 역할을 합니다.

예를 들어

세포 주기 조절,

DNA 손상 반응,

세포 사멸,

대사 과정 등이 포함됩니다.

또한

생체시계 타이밍 시스템은

암 치료의 효과와 독성을 조절합니다.

암 치료에서 크로노테라피(시간 기반 치료)는

화학요법, 방사선 치료, 기타 치료적 개입을 특정 간격으로 투여하여

효과를 극대화하고 부작용을 최소화하는 방법을 포함합니다.

이 접근 방식은

DNA 복구, 세포 주기 진행, 약물 대사 등

세포 과정의 생체시계 변동을 활용합니다.

전임상 및 임상 연구에서 크로노테라피는

시스플라틴과 5-플루오로우라실과 같은 화학요법제의 치료 지수를 유의미하게 개선함으로써

항암 활성을 강화하고

독성을 감소시키는 것으로 입증되었습니다.

추가 연구는

암의 생체 리듬 조절 메커니즘을 규명하고

개인의 생체 리듬 프로파일 맞춤형 강력한 크로노테라피 프로토콜을 개발하는 것이 필요하며,

이는 암 치료를 더 효과적이고 개인화된 전략으로 전환할 수 있습니다.

Introduction

Definition and overview of circadian rhythms and their biological significance

Circadian rhythms are intrinsic, endogenously driven cycles that span approximately 24 h, governing a multitude of physiological and behavioral processes in living organisms. The term comes from the Latin words “circa,” meaning “around,” and “diem,” meaning “day.” These rhythms are orchestrated by the circadian clock, a sophisticated system primarily located in the suprachiasmatic nucleus (SCN) of the hypothalamus in mammals. The SCN receives direct input from external cues, predominantly light, enabling the synchronization of internal biological clocks to the external environment [1, 2]. This synchronization is vital for the regulation of sleep–wake cycles, hormone release, metabolism, and various other bodily functions. The timing of these processes is dependent on the circadian phase, which determines when specific biological activities, such as sleep or hormone secretion, occur within the 24-h cycle [3, 4].

Utilizing essential clock genes and their protein products, including CLOCK, BMAL1, PER, and CRY, the circadian clock functions at the molecular level through a transcription-translation feedback loop [5–7]. The way these genes interact results in oscillations in gene expression‎, which in turn trigger rhythmic physiological functions. As people age, their circadian rhythm changes, which is linked to a host of age-related illnesses including metabolic syndrome, cancer, heart disease, neurological disorders, and an increased risk of infection. Moreover, disruptions to these rhythms, whether due to genetic mutations, environmental factors, or lifestyle choices, can have profound effects on health, leading to a range of disorders including sleep disorders, metabolic syndrome, cardiovascular diseases, neurological diseases and cancer [8, 9].

소개생체 리듬의 정의 및 생물학적 중요성

생체 리듬은

약 24시간 주기로 반복되는 내재적, 내인성 주기로,

생물체의 다양한 생리적 및 행동적 과정을 조절합니다.

이 용어는 라틴어 “circa”(주변)와 “diem”(날)에서 유래했습니다.

이러한 리듬은 주로

포유류의 뇌하수체 상부 시교차핵(SCN)에 위치한 생체 리듬 시계에 의해 조절됩니다.

SCN은

주로 빛과 같은 외부 신호로부터 직접적인 입력을 받아

내부 생물학적 시계를 외부 환경과 동기화합니다 [1, 2].

이 동기화는

수면-각성 주기,

호르몬 분비,

대사, 그리고

다양한 신체 기능의 조절에 필수적입니다.

이러한 과정의 시기는

24시간 주기 내에서 특정 생물학적 활동(예: 수면 또는 호르몬 분비)이 발생하는 시점을 결정하는

생체 리듬 단계에 따라 달라집니다 [3, 4].

CLOCK, BMAL1, PER, CRY 등 필수 시계 유전자와

그 단백질 산물을 활용해 생체 시계는

전사-번역 피드백 루프를 통해 분자 수준에서 기능합니다[5–7].

이 유전자들의 상호작용은

유전자 발현의 진동을 유발하며,

이는 다시 리듬적인 생리적 기능을 촉발합니다.

사람이 노화함에 따라 생체 리듬이 변화하며,

이는 대사 증후군, 암, 심장 질환, 신경계 장애, 감염 위험 증가 등

다양한 노화 관련 질환과 연관되어 있습니다.

또한 유전적 변이, 환경 요인, 생활 방식 선택 등으로 인한 리듬의 교란은

건강에 심각한 영향을 미쳐

수면 장애, 대사 증후군, 심혈관 질환, 신경계 질환, 암 등

다양한 질환을 유발할 수 있습니다 [8, 9].

Introduction to the concept of chronotherapy in the context of cancer treatment

Chronotherapy is an emerging therapeutic strategy that leverages the principles of circadian biology in optimizing the timing of medical treatments to enhance their efficacy and minimize side effects. In the context of cancer treatment, chronotherapy involves administering chemotherapy, radiation therapy, or other therapeutic interventions at specific times of the day when cancer cells are most vulnerable, and normal cells are least susceptible to damage [10, 11]. The rationale behind this approach is rooted in the understanding that cellular processes, including DNA repair, cell cycle progression, and drug metabolism, exhibit circadian variations [12, 13].

The application of chronotherapy in oncology has shown promising results in both preclinical and clinical studies. For example, specific timing of drug administration has been demonstrated to significantly improve the therapeutic index of various chemotherapeutic agents, such as cisplatin, 5-fluorouracil (5-FU), and doxorubicin, by enhancing their anticancer activity while reducing toxicity to normal tissues [14, 15]. Moreover, chronotherapy has been found to mitigate adverse effects commonly associated with cancer treatments, such as gastrointestinal toxicity, myelosuppression, and cardiotoxicity, thereby improving patient quality of life and treatment adherence [16, 17].

암 치료 맥락에서의 크로노테라피 개념 소개

크로노테라피는 생체 리듬의 원리를 활용해

의료 치료의 시기를 최적화하여

치료 효과를 극대화하고 부작용을 최소화하는 새로운 치료 전략입니다.

암 치료 맥락에서 크로노테라피는

암 세포가 가장 취약하고

정상 세포가 손상에 가장 덜 민감한 하루 중 특정 시간에

화학요법, 방사선 치료, 기타 치료적 개입을 투여하는 것을 포함합니다 [10, 11].

이 접근법의 근거는

DNA 복구, 세포 주기 진행, 약물 대사 등

세포 과정이 생체 리듬 변동을 보인다는 이해에 뿌리를 두고 있습니다 [12, 13].

종양학 분야에서 크로노테라피의 적용은 전임상 및 임상 연구에서 유망한 결과를 보여주었습니다. 예를 들어, 약물 투여 시점을 특정 시간대에 맞추는 것이 시스플라틴, 5-플루오로우라실(5-FU), 도ксо루비신 등 다양한 화학요법제의 치료 지수를 크게 개선하는 것으로 입증되었습니다. 이는 정상 조직에 대한 독성을 줄이면서 항암 활성을 강화함으로써 달성되었습니다 [14, 15]. 또한, 크로노테라피는 암 치료와 관련된 일반적인 부작용인 위장관 독성, 골수 억제, 심장 독성을 완화시켜 환자의 삶의 질과 치료 순응도를 개선하는 것으로 나타났습니다 [16, 17].

The relationship between circadian rhythms and cancer incidence, progression, and treatment response

Emerging evidence suggests a profound link between circadian rhythms and cancer, influencing not only the incidence and progression of the disease but also the response to treatment. Disruptions in circadian rhythms, whether due to genetic alterations, environmental factors such as shift work, or lifestyle habits, have been associated with an increased risk of developing various cancers [18, 19]. For instance, epidemiological studies have shown that individuals with chronic circadian misalignment, such as night shift workers, have a higher incidence of breast, prostate, and colorectal cancers [20, 21].

At the cellular level, the circadian clock regulates several pathways implicated in tumorigenesis, including cell cycle control, DNA damage response, apoptosis, and metabolism [13, 22]. Dysregulation of these pathways can lead to uncontrolled cell proliferation, genomic instability, and enhanced survival of cancer cells. Moreover, circadian disruption can influence the tumor microenvironment, including immune response and angiogenesis, further contributing to cancer progression [23–25] (Fig. 1).

생체 리듬과 암 발생, 진행, 치료 반응 간의 관계

최근 연구 결과는 생체 리듬과 암 사이에 깊은 연관성이 있음을 시사하며, 이는 질병의 발생과 진행뿐만 아니라 치료 반응에도 영향을 미칩니다.

생체 리듬의 교란은 유전적 변이, 교대 근무와 같은 환경적 요인, 생활 습관 등으로 인해 발생하며,

다양한 암의 발병 위험 증가와 연관되어 있습니다 [18, 19].

예를 들어, 역학 연구 결과,

만성 생체 리듬 불일치(예: 야간 근무자)를 가진 개인은

유방암, 전립선암, 대장암의 발병률이 더 높은 것으로 나타났습니다 [20, 21].

세포 수준에서 생체 리듬 시계는

종양 발생과 관련된 여러 경로를 조절합니다.

이는

세포 주기 조절, DNA 손상 반응, 세포 사멸, 대사 등이

포함됩니다 [13, 22].

이러한 경로의 조절 장애는

무분별한 세포 증식,

유전체 불안정성,

암 세포의 생존력 강화로 이어질 수 있습니다.

또한 생체 리듬 장애는 면역 반응과 혈관新生과 같은

종양 미세 환경에 영향을 미쳐 암 진행을 더욱 촉진할 수 있습니다 [23–25] (그림 1).

Fig. 1.

Role of BMAL1-CLOCK in cancer.

This flowchart illustrates the central role of circadian clock proteins BMAL1 and CLOCK in regulating cancer progression through various molecular pathways. BMAL1 activates pro-cancer pathways like c-Myc, Wnt/β-catenin, and Akt/mTOR, promoting tumor growth, progression, and metastasis. Specific cancers, such as liver cancer and intestinal cancer, are influenced by interactions with factors like HNF4-α and TAMs, respectively. On the other hand, the clock protein Rev-ERBα/β acts as an inhibitor of BMAL1, offering potential tumor-suppressive effects. The diagram also highlights the circadian clock’s role in regulating the Unfolded Protein Response (UPR), which impacts tumor survival. Overall, the circadian clock influences both cancer-promoting and inhibiting mechanisms, making it a potential target for therapeutic intervention.

BMAL1-CLOCK의 암에서의 역할.

이 흐름도는 BMAL1과 CLOCK이라는 생체 시계 단백질이 

다양한 분자 경로를 통해 암 진행을 조절하는 중심 역할을 설명합니다. 

BMAL1은 

c-Myc, Wnt/β-catenin, Akt/mTOR와 같은 암 촉진 경로를 활성화하여 

종양 성장, 진행, 및 전이를 촉진합니다. 

간암과 장암과 같은 특정 암은 각각 

HNF4-α와 TAMs와 같은 요인과의 상호작용에 의해 영향을 받습니다. 

반면, 

시계 단백질 Rev-ERBα/β는 

BMAL1의 억제제로 작용하여 잠재적인 종양 억제 효과를 제공합니다. 

이 도표는 

시계 단백질이 종양 생존에 영향을 미치는 

미접힘 단백질 반응(UPR) 조절에도 관여함을 강조합니다. 

전반적으로 시계 단백질은 

암 촉진 및 억제 메커니즘 모두에 영향을 미치며, 

이는 치료적 개입의 잠재적 표적이 될 수 있습니다.

Figure created with BioRender.com

A deeper examination of the molecular interactions reveals that the circadian clock proteins BMAL1 and CLOCK are central regulators of cancer progression, influencing a variety of signaling pathways that promote or inhibit tumor growth. BMAL1 and CLOCK form a transcriptional complex that controls the expression‎ of various genes involved in cellular functions such as metabolism, DNA repair, and the cell cycle. However, when dysregulated, they can contribute to oncogenic processes [12, 13].

BMAL1, in particular, is a key player in activating several pro-cancer pathways. One of the most critical is the c-Myc pathway, which regulates cell growth and division. Overexpression‎ of c-Myc, driven by BMAL1, can lead to uncontrolled cell proliferation, a hallmark of cancer. This is particularly important in cancers such as intestinal cancer and liver cancer, where abnormal BMAL1 activity can initiate or accelerate tumor progression. In addition to c-Myc, BMAL1 also activates the Wnt/β-catenin pathway, which is involved in cell fate determination and tissue regeneration. Aberrations in this pathway are linked to increased tumorigenesis and tumor metastasis, allowing cancer cells to invade surrounding tissues and spread to distant organs [13].

Another significant interaction involves the Akt/mTOR pathway, which is crucial for regulating cell survival, growth, and metabolism. BMAL1-mediated activation of this pathway helps tumors resist apoptosis (programmed cell death) and enhances their metabolic flexibility, enabling them to thrive in nutrient-poor environments. Additionally, p53, a well-known tumor suppressor, is modulated by BMAL1 and its downstream signaling. Disruptions in BMAL1 can reduce p53 activity, further diminishing the cell’s ability to respond to DNA damage and initiate apoptosis in abnormal cells [13, 16].

The Unfolded Protein Response (UPR) is another important mechanism through which BMAL1 influences cancer progression. The UPR is activated in response to stress in the endoplasmic reticulum, often due to increased protein synthesis or misfolding. In cancer cells, BMAL1 can upregulate the UPR, helping the tumor cells survive under stressful conditions, such as hypoxia or nutrient deprivation, by improving their ability to fold proteins correctly or degrade misfolded proteins [22].

In contrast, the clock protein Rev-ERBα/β plays a tumor-suppressive role by counteracting the actions of BMAL1. Rev-ERBα/β works to repress BMAL1 activity, thus inhibiting the pro-cancer pathways BMAL1 regulates. By inhibiting the c-Myc, Wnt/β-catenin, and Akt/mTOR pathways, Rev-ERBα/β limits tumor growth and may slow down metastasis. In effect, this forms a balancing act between BMAL1’s promotion of cancer progression and Rev-ERBα/β’s tumor-suppressing effects. This interaction highlights a potential therapeutic avenue for targeting the circadian clock in cancer treatment, as enhancing Rev-ERBα/β activity or suppressing BMAL1 could potentially inhibit tumor growth [16, 22].

Furthermore, external factors such as HNF4-α and tumor-associated macrophages (TAMs) influence the activity of BMAL1 in various cancers. HNF4-α, a nuclear receptor involved in liver development and function, interacts with BMAL1 to regulate metabolic processes in liver cancer, potentially promoting tumorigenesis. TAMs, which are immune cells present within the tumor microenvironment, also interact with BMAL1, often leading to a pro-inflammatory state that fosters tumor progression. While BMAL1’s role in activating cancer-related pathways represents a significant risk, understanding its regulatory mechanisms also provides therapeutic opportunities. Targeting BMAL1’s downstream effects, such as the Akt/mTOR or Wnt/β-catenin pathways, could provide a focused approach for combating cancer progression. Similarly, enhancing the tumor-suppressive actions of Rev-ERBα/β represents another promising strategy [13, 16, 22].

However, the complexity of these molecular interactions also presents challenges. BMAL1 and CLOCK are integral to the regulation of normal circadian rhythms, and their complete inhibition could lead to unintended consequences, such as metabolic disorders or impaired immune function. Therefore, therapies targeting circadian clock proteins would need to strike a delicate balance between suppressing cancer-promoting pathways and preserving the essential functions of the circadian system. Moreover, patient variability in circadian rhythm regulation may necessitate highly personalized treatment approaches, which could complicate the clinical implementation of such therapies [16, 22].

The circadian timing system also plays a crucial role in modulating the efficacy and toxicity of cancer treatments. The expression‎ of drug-metabolizing enzymes, transporters, and targets exhibits circadian variations, affecting the pharmacokinetics and pharmacodynamics of chemotherapeutic agents [26–28]. For example, the enzyme dihydropyrimidine dehydrogenase (DPD), which metabolizes 5-FU, shows diurnal variations in activity, influencing the drug’s efficacy and toxicity profile depending on the time of administration [10, 29].

Furthermore, circadian rhythms across mammalian species, including humans can affect the DNA repair mechanisms in both normal and cancer cells. The capacity for DNA repair fluctuates throughout the day, with peak activity typically occurring during the night when cells are less likely to be actively dividing [30, 31]. This temporal variation suggests that timing DNA-damaging treatments, such as radiation therapy, to coincide with periods of low DNA repair activity in cancer cells could enhance therapeutic outcomes while sparing normal tissues.

In conclusion, the complex connection that exists between circadian rhythms and cancer highlights the possibility of chronotherapy as a paradigm-shifting treatment for cancer. By aligning treatment schedules with the body’s biological rhythms, chronotherapy aims to maximize the therapeutic benefits of cancer treatments while minimizing their adverse effects. Further research is needed to completely understand the processes behind the circadian regulation of cancer and to create effective chronotherapeutic regimens customized to each patient’s unique circadian profile. These developments have the potential to revolutionize cancer care by providing more individualized and efficient treatment plans.

분자 상호작용을 더 깊이 분석한 결과,

생체 시계 단백질 BMAL1과 CLOCK이

암 진행의 핵심 조절자로 작용하며,

종양 성장 촉진 또는 억제에 관여하는 다양한 신호 전달 경로를 조절한다는 것이 밝혀졌습니다.

BMAL1과 CLOCK은

대사, DNA 복구, 세포 주기 등 세포 기능에 관여하는 다양한 유전자 발현을 조절하는

전사 복합체를 형성합니다.

그러나

이들이 조절 장애를 일으킬 경우

암 발생 과정에 기여할 수 있습니다 [12, 13].

특히 BMAL1은

여러 암 촉진 경로를 활성화하는 핵심 역할을 합니다.

가장 중요한 경로 중 하나는

세포 성장과 분열을 조절하는 c-Myc 경로입니다.

BMAL1에 의해 유도된 c-Myc의 과발현은

암의 특징인 무분별한 세포 증식을 유발할 수 있습니다.

이는 장암과 간암과 같은 암에서 특히 중요합니다.

BMAL1의 이상 활동은

종양 진행을 초래하거나 가속화할 수 있습니다.

c-Myc 외에도 BMAL1은

세포 운명 결정과 조직 재생에 관여하는 Wnt/β-catenin 경로를 활성화합니다.

이 경로의 이상은 종양 발생과 종양 전이를 증가시켜

암 세포가 주변 조직을 침범하고 먼 장기로 확산되도록 합니다 [13].

Wnt/β-catenin 경로는 배아 발달과 성인 조직의 항상성에 중요한 역할을 하는 단백질 가족으로 구성되어 있습니다. Wnt/β-catenin 신호전달 경로의 조절 장애는 암과 비암성 질환을 포함한 다양한 심각한 질환으로 이어질 수 있습니다. Wnt/β-catenin에 대한 다양한 측면을 다룬 많은 논문이 존재하지만, 종양 및 질환에서 Wnt/β-catenin 신호전달 경로의 기원, 구성, 기능, 임상 시험을 포괄적으로 검토한 체계적인 리뷰는 부족합니다. 본 논문에서는 최신 연구 결과를 바탕으로 위의 다섯 가지 측면을 종합적으로 검토합니다. 마지막으로, 질병 치료를 위한 Wnt 신호전달 경로를 표적으로 하는 소분자 화합물의 개발에 대한 도전 과제와 기회를 제안합니다.

또 다른 중요한 상호작용은

세포 생존, 성장, 대사 조절에 필수적인

Akt/mTOR 경로와 관련됩니다.

BMAL1에 의해 활성화된 이 경로는

종양이 아포토시스(프로그램된 세포 사멸)를 저항하고

대사 유연성을 높여 영양분이 부족한 환경에서도 생존할 수 있도록 돕습니다.

또한,

잘 알려진 종양 억제인자 p53은

BMAL1 및 그 하류 신호전달에 의해 조절됩니다.

BMAL1의 장애는 p53 활성을 감소시켜

세포가 DNA 손상에 반응하고 비정상 세포에서 아포토시스를 유발하는 능력을

더욱 약화시킵니다 [13, 16].

미접힘 단백질 반응(UPR)은

BMAL1이 암 진행에 영향을 미치는 또 다른 중요한 메커니즘입니다.

UPR은 내소체 내 스트레스에 반응하여 활성화되며,

이는 단백질 합성 증가나 단백질 변형으로 인해 발생합니다.

암 세포에서 BMAL1은

UPR을 활성화시켜 저산소증이나 영양 결핍과 같은 스트레스 조건에서 종

양 세포가 생존할 수 있도록 돕습니다.

이는

단백질의 올바른 접힘을 개선하거나

변형된 단백질을 분해하는 능력을 향상시킵니다 [22].

반면,

시계 단백질 Rev-ERBα/β는

BMAL1의 작용을 억제함으로써 종양 억제 역할을 합니다.

Rev-ERBα/β는 BMAL1의 활성을 억제하여

BMAL1이 조절하는 종양 촉진 경로를 차단합니다.

c-Myc, Wnt/β-catenin, 및 Akt/mTOR 경로를 억제함으로써

Rev-ERBα/β는 종양 성장 제한과 전이 속도 감소를 유도할 수 있습니다.

결국

이는 BMAL1의 암 진행 촉진 효과와

Rev-ERBα/β의 종양 억제 효과 사이의 균형 작용을 형성합니다.

이 상호작용은 암 치료에서 생체 리듬 시계를 표적으로 삼는 잠재적 치료 전략을 제시합니다.

Rev-ERBα/β 활성을 증강하거나

BMAL1을 억제하면 종양 성장 억제가 가능할 수 있습니다 [16, 22].

또한

HNF4-α와 종양 연관 대식세포(TAMs)와 같은 외부 요인은

다양한 암에서 BMAL1의 활성에 영향을 미칩니다.

간 발달과 기능에 관여하는 핵 수용체인 HNF4-α는

간암에서 BMAL1과 상호작용하여 대사 과정을 조절하며,

이는 종양 발생을 촉진할 수 있습니다.

종양 미세환경에 존재하는 면역 세포인 TAMs도

BMAL1과 상호작용하여 종양 진행을 촉진하는 염증 상태를 유발합니다.

BMAL1이 암 관련 경로를 활성화하는 역할은 중요한 위험 요인이지만,

그 조절 메커니즘을 이해하는 것은 치료적 기회를 제공합니다.

BMAL1의 하류 효과인 Akt/mTOR 또는 Wnt/β-catenin 경로를 표적화하는 것은

암 진행을 억제하는 집중적인 접근법을 제공할 수 있습니다.

마찬가지로

Rev-ERBα/β의 종양 억제 작용을 강화하는 것은

또 다른 유망한 전략입니다 [13, 16, 22].

그러나 이러한 분자 간 상호작용의 복잡성은 도전 과제를 제기합니다.

BMAL1과 CLOCK은 정상적인 생체 리듬 조절에 필수적이며,

이들의 완전한 억제는 대사 장애나 면역 기능 저하와 같은 의도하지 않은 결과를 초래할 수 있습니다.

따라서

생체 리듬 단백질을 표적으로 하는 치료법은

암 촉진 경로를 억제하는 동시에

생체 리듬 시스템의 필수 기능을 유지하는 섬세한 균형을 유지해야 합니다.

또한 환자의 생체 리듬 조절 변이성은

고도로 개인화된 치료 접근법이 필요할 수 있으며,

이는 이러한 치료법의 임상 적용을 복잡하게 만들 수 있습니다 [16, 22].

생체 리듬 타이밍 시스템은

암 치료의 효능과 독성을 조절하는 데도 중요한 역할을 합니다.

약물 대사 효소, 운반체, 표적의 발현은 생체리듬 변동을 보이며,

이는 화학요법제의 약동학 및 약력학에 영향을 미칩니다 [26–28].

예를 들어,

5-FU를 대사하는 효소인 디히드로피리미딘 탈수소효소(DPD)는 활동에 일일 변동을 보이며,

투여 시간에 따라 약물의 효능과 독성 프로파일에 영향을 미칩니다 [10, 29].

또한

인간을 포함한 포유류 종의 생체 리듬은

정상 세포와 암 세포 모두의 DNA 복구 메커니즘에 영향을 미칩니다.

DNA 복구 능력은 하루 종일 변동되며,

세포 분열이 덜 활발한 밤에 활동이 정점에 달합니다 [30, 31].

이 시간적 변동은

방사선 치료와 같은 DNA 손상 치료를

암 세포의 DNA 복구 활동이 낮은 시기와 맞추는 것이

치료 효과를 향상시키며

정상 조직을 보호할 수 있음을 시사합니다.

결론적으로, 생체 리듬과 암 사이의 복잡한 연관성은 암 치료의 패러다임을 전환할 수 있는chronotherapy(생체 리듬 치료)의 가능성을 강조합니다. 생체 리듬에 맞춰 치료 일정을 조정함으로써, chronotherapy는 암 치료의 치료 효과를 극대화하고 부작용을 최소화하는 것을 목표로 합니다. 암의 생체 리듬 조절 메커니즘을 완전히 이해하고 각 환자의 고유한 생체 리듬 프로파일에 맞춤형 효과적인 크로노테라피 프로토콜을 개발하기 위해 추가 연구가 필요합니다. 이러한 발전은 더 개인화되고 효율적인 치료 계획을 제공함으로써 암 치료를 혁신할 잠재력을 가지고 있습니다.

Circadian rhythms: biological mechanisms and cancerDescription of the molecular mechanisms underlying circadian rhythms, including the central and peripheral clocks

Circadian rhythms are driven by a complex network of molecular mechanisms that synchronize physiological processes to the 24-h day-night cycle and controlled by the central circadian clock resides in the SCN of the hypothalamus. This central clock orchestrates peripheral clocks located in almost every tissue and organ, maintaining systemic temporal harmony [30, 32]. The SCN receives photic information directly from the retina, allowing it to reset and synchronize peripheral clocks through neural and hormonal signals, such as melatonin [33, 34].

At the molecular level, the circadian clock operates through a transcription-translation feedback loop involving core clock genes and proteins, including CLOCK, BMAL1, PER, and CRY. CLOCK and BMAL1 form a heterodimer that drives the expression‎ of PER and CRY genes. The PER and CRY proteins accumulate in the cytoplasm, eventually translocating to the nucleus where they inhibit the activity of the CLOCK:BMAL1 complex, thus suppressing their own transcription. This feedback loop creates approximately 24-h oscillations in the expression‎ of clock-controlled genes, which regulate various physiological processes [35, 36] (Fig. 2).

생체 리듬: 생물학적 메커니즘과 암생체 리듬의 분자적 메커니즘 설명, 중앙 및 주변 시계 포함

생체 리듬은

24시간 주기적 주야 주기에 생리적 과정을 동기화하는 복잡한 분자적 메커니즘 네트워크에 의해 조절되며,

이 네트워크는 뇌하수체에 위치한 SCN(시계 신경핵)에 있는

중앙 생체 리듬 시계에 의해 통제됩니다.

이 중앙 시계는

거의 모든 조직과 기관에 위치한 주변 시계를 조정하여 체계적인 시간적 조화를 유지합니다 [30, 32].

SCN은 망막으로부터 직접 광 정보를 받아

멜라토닌과 같은 신경 및 호르몬 신호를 통해

주변 시계를 재설정하고 동기화합니다 [33, 34].

분자 수준에서 생체시계는

CLOCK, BMAL1, PER, CRY와 같은

핵심 생체시계 유전자와 단백질을 포함한

전사-번역 피드백 루프를 통해 작동합니다.

CLOCK과 BMAL1은 이종 이합체를 형성하여

PER과 CRY 유전자의 발현을 촉진합니다.

PER 및 CRY 단백질은

세포질에 축적된 후 핵으로 이동하여

CLOCK:BMAL1 복합체의 활성을 억제함으로써 자신의 전사를 억제합니다.

이 피드백 루프는

시계 조절 유전자의 발현에 약 24시간 주기의 진동을 생성하며,

이는 다양한 생리적 과정을 조절합니다 [35, 36] (그림 2).

Fig. 2.

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Molecular mechanisms of circadian rhythm. The figure illustrates the central molecular mechanism of the circadian clock, driven by a feedback loop involving key proteins and genes that regulate the body’s 24-h rhythm. The core components are CLOCK and BMAL1, which form a complex in the nucleus and bind to DNA at specific sites to promote the transcription of clock genes like PER (Period) and CRY (Cryptochrome). These genes produce PER and CRY proteins, which accumulate during the night. As PER and CRY proteins build up, they are phosphorylated by CK1δ (Casein Kinase 1 delta) and move into the nucleus, where they inhibit the CLOCK-BMAL1 complex, halting their own production in a negative feedback loop. Over time, the proteins degrade, releasing the inhibition and allowing the cycle to start again the next day. Additional regulators like Rev-Erbα/β and RORs help fine-tune the cycle by controlling BMAL1 expression‎—Rev-Erbα/β inhibits BMAL1, while RORs promote it. This clock mechanism maintains a roughly 24-h cycle that regulates key processes like sleep–wake cycles, hormone secretion, and metabolism, ensuring alignment with the external day-night cycle.

생체 리듬의 분자적 메커니즘. 

이 그림은 핵심 단백질과 유전자들이 24시간 리듬을 조절하는 피드백 루프를 통해 작동하는 생체 리듬의 중심 분자적 메커니즘을 보여줍니다. 핵심 구성 요소는 CLOCK과 BMAL1로, 이들은 핵 내에서 복합체를 형성하고 특정 부위에 DNA에 결합하여 PER(Period)와 CRY(Cryptochrome)와 같은 시계 유전자의 전사를 촉진합니다. 이 유전자들은 PER과 CRY 단백질을 생성하며, 이 단백질들은 밤 동안 축적됩니다. PER과 CRY 단백질이 축적되면 CK1δ(Casein Kinase 1 delta)에 의해 인산화되어 핵으로 이동해 CLOCK-BMAL1 복합체를 억제함으로써 자신의 생산을 중단시키는 음의 피드백 루프를 형성합니다. 시간이 지나면 이 단백질들이 분해되어 억제가 해제되며, 다음 날 사이클이 다시 시작됩니다. Rev-Erbα/β와 RORs와 같은 추가 조절 인자는 BMAL1 발현을 조절하여 주기를 미세 조정합니다. Rev-Erbα/β는 BMAL1을 억제하는 반면, RORs는 이를 촉진합니다. 이 시계 메커니즘은 수면-각성 주기, 호르몬 분비, 대사 등 핵심 과정을 조절하는 약 24시간 주기를 유지하여 외부 낮-밤 주기와 일치하도록 합니다.

Figure created with BioRender.com

The accompanying figure illustrates the intricate feedback loop central to the regulation of circadian rhythms at the molecular level. At the core of this loop is the CLOCK-BMAL1 complex, which acts as a transcription factor in the nucleus. During the day, this complex binds to specific DNA sequences known as E-boxes, with a consensus sequence of CTCGAG. The binding of CLOCK and BMAL1 to these E-boxes initiates the transcription of key clock genes, specifically the Period (PER) and Cryptochrome (CRY) genes, which encode proteins crucial for maintaining the circadian rhythm [30, 32, 34].

As the day progresses, the synthesis of PER and CRY proteins occurs in the cytoplasm. The accumulation of these proteins is regulated by a phosphorylation process, primarily mediated by CK1δ (Casein Kinase 1 delta). This phosphorylation modifies the PER and CRY proteins, enhancing their stability and promoting their subsequent translocation into the nucleus. Once inside the nucleus, the PER and CRY proteins exert their primary function by inhibiting the activity of the CLOCK-BMAL1 complex. This inhibition is a critical regulatory step that effectively halts the transcription of PER and CRY, creating a negative feedback loop that is essential for circadian regulation. As night approaches, the levels of PER and CRY proteins gradually decrease due to proteolytic degradation processes. This degradation is essential for resetting the circadian clock for the next cycle. With the decline in PER and CRY levels, the inhibitory effect on CLOCK and BMAL1 is lifted, allowing these proteins to once again bind to the E-boxes and promote the transcription of PER and CRY genes. This cycle of activation and inhibition maintains the rhythmic oscillations in gene expression‎ that characterize the circadian rhythm, typically spanning approximately 24 h [33, 34].

The timing of these events is critical; the dynamics of the feedback loop ensure that the expression‎ of PER and CRY proteins follows a precise diurnal pattern. The ability of the CLOCK-BMAL1 complex to regulate its own activity through the action of PER and CRY not only establishes a self-sustaining mechanism but also provides a level of resilience against external environmental cues, thereby ensuring the synchronization of the internal biological clock with the external day-night cycle. This sophisticated regulatory system highlights the complexity of circadian biology and the importance of feedback mechanisms in maintaining temporal harmony within biological systems [30, 32, 34].

In addition to this primary loop, there are auxiliary feedback loops that enhance the robustness and precision of circadian rhythms. For example, the REV-ERB and ROR nuclear receptors form an additional loop that regulates the expression‎ of Bmal1. REV-ERBs inhibit Bmal1 transcription, while RORs activate it, providing fine-tuned control over the timing and amplitude of the circadian cycle. These secondary feedback loops ensure the stability of the clock and modulate other physiological pathways, such as lipid metabolism and inflammation [35, 36].

Peripheral clocks, although driven by the central clock, can be influenced by various environmental cues, such as feeding times, temperature, and physical activity [37]. These clocks regulate local tissue-specific functions, including metabolism, cell cycle, and hormone production, ensuring that each organ operates optimally in sync with the overall circadian system [37, 38].

동반된 그림은 분자 수준에서 생체 리듬 조절의 핵심인 복잡한 피드백 루프를 설명합니다. 이 루프의 중심에는 핵 내에서 전사 인자로 작용하는 CLOCK-BMAL1 복합체가 있습니다. 낮 동안 이 복합체는 CTCGAG라는 공통 시퀀스를 가진 특정 DNA 서열인 E-박스에 결합합니다. CLOCK과 BMAL1이 이 E-박스에 결합하면 시계 유전자인 Period (PER)와 Cryptochrome (CRY) 유전자의 전사가 시작됩니다. 이 유전자들은 생체 리듬을 유지하는 데 필수적인 단백질을编码합니다 [30, 32, 34].

하루가 진행됨에 따라 PER과 CRY 단백질의 합성이 세포질에서 발생합니다. 이 단백질의 축적은 주로 CK1δ(Casein Kinase 1 delta)에 의해 매개되는 인산화 과정에 의해 조절됩니다. 이 인산화는 PER과 CRY 단백질을 변형시켜 안정성을 높이고 이후 핵으로의 이동을 촉진합니다. 핵 내로 이동한 PER과 CRY 단백질은 CLOCK-BMAL1 복합체의 활성을 억제하는 주요 기능을 수행합니다. 이 억제는 PER과 CRY의 전사를 효과적으로 중단시키는 중요한 조절 단계로, 생체 리듬 조절에 필수적인 음성 피드백 루프를 형성합니다. 밤이 다가오면 PER과 CRY 단백질의 수준은 단백질 분해 과정에 의해 점차 감소합니다. 이 분해는 다음 주기를 위해 생체 리듬 시계를 재설정하는 데 필수적입니다. PER 및 CRY 수준이 감소함에 따라 CLOCK과 BMAL1에 대한 억제 효과가 해제되어, 이 단백질들이 다시 E-박스에 결합하여 PER 및 CRY 유전자의 전사를 촉진합니다. 이 활성화와 억제의 사이클은 유전자 발현의 리듬적 진동을 유지하며, 이는 일반적으로 약 24시간 동안 지속되는 생체 리듬의 특징입니다 [33, 34].

이 사건들의 시기는 매우 중요합니다. 피드백 루프의 역학은 PER 및 CRY 단백질의 발현이 정확한 일일 패턴을 따르도록 보장합니다. CLOCK-BMAL1 복합체가 PER 및 CRY의 작용을 통해 자신의 활동을 조절하는 능력은 단순히 자체 유지 메커니즘을 확립하는 것뿐 아니라 외부 환경 신호에 대한 내성을 제공하여 내부 생물학적 시계와 외부 낮-밤 주기 간의 동기화를 보장합니다. 이 복잡한 조절 시스템은 생물학적 시스템 내 시간적 조화를 유지하는 데 피드백 메커니즘의 중요성을 강조하며, 생체 리듬 생물학의 복잡성을 보여줍니다 [30, 32, 34].

이 주요 루프 외에도 생체 리듬의 견고성과 정밀도를 높이는 보조 피드백 루프가 존재합니다. 예를 들어, REV-ERB와 ROR 핵 수용체는 Bmal1의 발현을 조절하는 추가 루프를 형성합니다. REV-ERBs는 Bmal1 전사를 억제하는 반면, RORs는 이를 활성화하여 생체 리듬 주기의 시기와 진폭을 정밀하게 조절합니다. 이러한 보조 피드백 루프는 시계의 안정성을 보장하고 지방 대사 및 염증과 같은 다른 생리적 경로를 조절합니다 [35, 36].

주변 시계는 중앙 시계에 의해 구동되지만, 식사 시간, 온도, 신체 활동 등 다양한 환경적 신호에 영향을 받을 수 있습니다[37]. 이러한 시계는 대사, 세포 주기, 호르몬 생산 등 조직 특이적 기능을 조절하여 각 장기가 전체 생체 리듬 시스템과 동기화되어 최적의 상태로 작동하도록 합니다[37, 38].

The impact of circadian disruption on cancer risk

Circadian disruption, often caused by modern lifestyle factors such as shift work, exposure to artificial light at night, and irregular sleep patterns, has been linked to an increased risk of various cancers. Epidemiological studies have provided compelling evidence that night shift work, which involves exposure to light during nighttime hours, disrupts the circadian system and is associated with higher incidences of breast, prostate, and colorectal cancers [39]. This disruption is believed to interfere with melatonin production, a hormone with oncostatic properties, thereby increasing cancer susceptibility [40].

Mechanistically, circadian disruption affects the expression‎ of clock genes and disrupts the regulation of genes involved in cell cycle control, DNA repair, and apoptosis. For example, shift work has been shown to alter the expression‎ of PER and CRY genes, leading to dysregulated cell cycle progression and impaired DNA repair mechanisms, which can contribute to genomic instability and tumorigenesis [41]. Additionally, exposure to light at night suppresses melatonin production, which not only disrupts sleep but also removes the protective oncostatic effects of melatonin, further promoting cancer development [42].

Lifestyle factors such as irregular eating patterns and physical inactivity can also disrupt peripheral clocks, exacerbating the risk of cancer. Irregular meal times can desynchronize metabolic processes, leading to metabolic disorders that are linked to increased cancer risk. For instance, obesity and type 2 diabetes, conditions associated with disrupted circadian rhythms, have been identified as risk factors for several types of cancer [43].

Mechanistic insights into how circadian rhythms influence cancer cell cycle, DNA repair, and metabolism

Circadian rhythms exert a profound influence on various cellular processes that are critical to cancer development and progression, including the cell cycle, DNA repair, and metabolism. The cell cycle is tightly regulated by circadian genes, with clock proteins influencing the timing of cell division and the expression‎ of cell cycle regulators. CLOCK and BMAL1 have been shown to control the expression‎ of genes such as p21 and p53, which are crucial for cell cycle arrest and apoptosis [44]. Disruption of circadian regulation can lead to uncontrolled cell proliferation, a hallmark of cancer. DNA repair mechanisms are also under circadian control. The efficiency of DNA repair fluctuates throughout the day, with peak activity occurring during periods when cells are less likely to be actively dividing. This temporal regulation ensures that DNA damage is efficiently repaired before cell division, maintaining genomic stability [45]. For instance, the nucleotide excision repair pathway, responsible for repairing UV-induced DNA damage, is influenced by the circadian clock, with genes such as XPA showing circadian oscillations in expression‎. Disruption of circadian rhythms can impair DNA repair processes, leading to the accumulation of mutations and increased cancer risk [46] (Fig. 3).

Fig. 3.

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Impact of circadian clock on cell cycle components. The diagram illustrates the pivotal role of circadian clock proteins CLOCK and BMAL1 in regulating cellular processes such as the cell cycle, DNA repair, and apoptosis. CLOCK and BMAL1 form a heterodimer that initiates the transcription of target genes, including PER2, crucial for maintaining circadian rhythms. This clock influences cell division across the G1, S, G2, and M phases by modulating key proteins like Cyclin B1 and CDK1, with WEE-1 kinase preventing premature entry into mitosis. Additionally, the CLOCK-BMAL1 complex interacts with the p53 pathway, regulating this tumor suppressor in response to DNA damage. The regulation of C-myc by CLOCK and BMAL1 further underscores their dual role in promoting and inhibiting growth. The involvement of Chk2 and ATM proteins in the DNA damage response highlights the interconnectedness of circadian rhythms with cellular stress responses. Overall, the figure emphasizes how the circadian clock ensures cellular integrity and prevents diseases, including cancer, by orchestrating these critical pathways. Figure created with BioRender.com

Metabolism is another critical aspect regulated by circadian rhythms. The circadian clock coordinates metabolic processes to anticipate and respond to nutrient availability, ensuring energy homeostasis. Key metabolic pathways, including glycolysis, lipid metabolism, and oxidative phosphorylation, are regulated by clock genes [47]. In cancer cells, circadian disruption can lead to metabolic reprogramming, supporting the enhanced energetic and biosynthetic demands of rapidly proliferating cells. For instance, the Warburg effect, a metabolic hallmark of cancer characterized by increased glycolysis and lactate production, has been linked to dysregulation of circadian genes such as MYC and HIF-1α [23].

Furthermore, the interaction between circadian rhythms and the tumor microenvironment plays a significant role in cancer progression. Circadian regulation of immune cell function, angiogenesis, and the extracellular matrix can influence tumor growth and metastasis [24, 48]. For example, the recruitment and activity of immune cells such as natural killer cells and T cells are modulated by circadian rhythms, affecting the immune surveillance and elimination of cancer cells [49].

In conclusion, the intricate relationship between circadian rhythms and cancer encompasses a multifaceted network of molecular mechanisms that regulate the cell cycle, DNA repair, and metabolism. Disruption of circadian rhythms through lifestyle factors or environmental influences can significantly impact cancer risk and progression. Understanding these mechanisms provides valuable insights into potential therapeutic strategies that leverage the principles of circadian biology, such as chronotherapy, to optimize cancer treatment and improve patient outcomes.

Circadian rhythms and cancer treatment efficacy

Overview of how the timing of cancer treatment can affect drug metabolism, toxicity, and efficacy

Circadian rhythms significantly influence the pharmacokinetics and pharmacodynamics of cancer treatments, including chemotherapy, radiotherapy, and targeted therapy. The timing of drug administration can affect drug absorption, distribution, metabolism, and excretion (ADME), as well as the sensitivity of cancer cells to therapeutic agents [50, 51]. These circadian variations are primarily driven by the oscillatory expression‎ of clock genes and their downstream targets, which regulate enzymes and transporters involved in drug metabolism and detoxification [52].

For instance, the activity of cytochrome P450 enzymes, which play a crucial role in drug metabolism, exhibits circadian variations, leading to fluctuations in drug plasma concentrations and therapeutic efficacy [28, 53]. Additionally, the expression‎ of ATP-binding cassette (ABC) transporters, responsible for drug efflux, also follows a circadian pattern, impacting drug accumulation in cancer cells and thus influencing toxicity and efficacy [54]. These circadian-regulated processes underscore the importance of timing in optimizing cancer treatment to enhance therapeutic outcomes and minimize adverse effects.

Discussion on the circadian modulation of chemotherapy, radiotherapy, and targeted therapy effectiveness

Chemotherapy, one of the mainstays of cancer treatment, has been extensively studied in the context of circadian rhythms. The timing of chemotherapy administration can significantly alter its therapeutic index by modulating drug toxicity and efficacy. One well-studied example is the anticancer drug 5-fluorouracil (5-FU), commonly used in the treatment of gastrointestinal cancers. Research has shown that both the efficacy and toxicity of 5-FU are strongly influenced by the time of day it is administered. In rodent models, administering 5-FU during the early rest phase (equivalent to the night in humans) significantly reduces its toxicity, while maintaining or even enhancing its antitumor activity [10, 55]. This temporal variation in drug response is closely tied to the circadian regulation of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU catabolism. DPD activity peaks during the rest phase, allowing for faster breakdown of 5-FU, thereby reducing drug accumulation and limiting damage to healthy tissues [56]. The circadian clock also governs key cellular processes such as DNA repair and cell division, which can affect the susceptibility of both cancerous and healthy cells to chemotherapy. During the rest phase, when normal cells exhibit higher rates of DNA repair and are less likely to be in the vulnerable phases of the cell cycle (such as mitosis), chemotherapy-induced damage is less severe. In contrast, cancer cells, which often have disrupted circadian rhythms, may remain vulnerable to treatment. This selective timing allows for enhanced targeting of tumor cells while protecting healthy tissues, thereby improving the therapeutic index of the drug (Fig. 4) [10, 55, 56].

Fig. 4.

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Implication of chronotherapeutic approach in improving tolerance and cytotoxicity of anticancer drugs. A Chronotissue tolerance in cancer treatment involves considering the fluctuating levels of key enzymes and biomarkers in host tissues. For instance, dihydropyrimidine dehydrogenase (DPD), responsible for eliminating 5-FU, and thymidine synthase (TS) exhibit opposing peak and trough levels, correlating with decreased toxicity during 5-FU therapy. Additionally, variations in daily levels of glutathione (GSH), a powerful antioxidant, serve as another important biomarker of host chronotolerance, particularly relevant when administering platinum-based drugs like oxaliplatin and cisplatin. Similarly, the efficacy of doxorubicin is more tolerable and highly efficacious in the morning dosage. B Chronotumor toxicity from anticancer agents involves exploiting daily rhythms in the tumor’s cell cycle. Various drugs designed to target specific phases of the cell cycle can be utilized, such as seliciclib for G1 phase, palbociclib for G-S phase transition, 5-FU for S phase, and docetaxel for M phase. Figure created with BioRender.com

시간 치료 접근법의 항암제 내성 및 독성 개선에 대한 함의.

A 암 치료에서의 시간 조직 내성은 호스트 조직 내 핵심 효소 및 생물표지자의 변동 수준을 고려하는 것을 포함합니다. 예를 들어, 5-FU를 제거하는 역할을 하는 디히드로피리미딘 탈수소효소(DPD)와 티미딘 합성효소(TS)는 반대되는 피크 및 저점 수준을 보이며, 이는 5-FU 치료 중 독성 감소와 관련이 있습니다. 또한 강력한 항산화제인 글루타티온(GSH)의 일일 수치 변동은 호스트 크로노내성의 중요한 바이오마커로 작용하며, 옥살리플라틴과 시스플라틴과 같은 플라티넘 기반 약물을 투여할 때 특히 중요합니다. 마찬가지로 도ксо루비신의 효능은 아침 투여 시 내약성이 더 우수하고 효과적입니다.

B 항암제의 크로노종양 독성은 종양 세포 주기의 일일 리듬을 활용하는 것을 포함합니다. 세포 주기의 특정 단계에 표적화되도록 설계된 다양한 약물이 활용될 수 있습니다. 예를 들어, G1 단계에 작용하는 셀리시클리브, G-S 단계 전환에 작용하는 팔보시클리브, S 단계에 작용하는 5-FU, M 단계에 작용하는 도세탁셀 등이 있습니다.

The chronotherapeutic approach to cancer treatment emphasizes the timing of drug administration to optimize therapeutic efficacy and minimize toxicity. This strategy considers the body’s natural rhythms, which can influence how patients metabolize drugs and how tumors respond to treatment. Chronotissue tolerance refers to the varying levels of enzymes and biomarkers within host tissues that can affect the efficacy and safety of chemotherapy. For example, dihydropyrimidine dehydrogenase (DPD) and thymidine synthase (TS) exhibit daily fluctuations that correlate with reduced toxicity during 5-FU therapy. Similarly, daily variations in glutathione (GSH) levels are relevant for patients receiving platinum-based drugs like oxaliplatin and cisplatin, affecting the body’s tolerance to oxidative stress. Doxorubicin also shows improved efficacy when administered in the morning [55, 56].

On the other hand, chronotumor toxicity focuses on exploiting the daily rhythms of the tumor cell cycle. Different anticancer drugs can be timed to target specific phases of the cell cycle, improving their effectiveness while reducing side effects. For instance, seliciclib targets the G1 phase, palbociclib affects the G1-S phase transition, 5-FU is effective during the S phase, and docetaxel targets the M phase. By aligning drug administration with these biological rhythms, clinicians can optimize treatment regimens, leading to better outcomes and enhanced patient quality of life [10, 55, 56].

Radiotherapy, another cornerstone of cancer treatment, also exhibits circadian variations in efficacy and toxicity. The DNA repair mechanisms, such as nucleotide excision repair (NER) and homologous recombination (HR), are under circadian control, with peak repair activities occurring at specific times of the day [57]. By aligning radiation delivery with periods of low DNA repair activity in cancer cells, radiotherapy can maximize DNA damage in tumors while sparing normal tissues, thereby enhancing therapeutic outcomes [58, 59].

Targeted therapies, including kinase inhibitors and monoclonal antibodies, are also influenced by circadian rhythms. The circadian regulation of cell cycle proteins and apoptotic pathways can affect the sensitivity of cancer cells to these therapies. For instance, the efficacy of the tyrosine kinase inhibitor imatinib has been shown to vary depending on the time of administration, with enhanced therapeutic effects observed when administered in alignment with the circadian expression‎ of its target, BCR-ABL [60].

Analysis of preclinical and clinical research supporting the concept of chronotherapy in the treatment of cancer

The concept of chronotherapy, which involves tailoring treatment schedules to the patient’s circadian rhythms, has garnered significant attention in both preclinical and clinical settings. Preclinical studies have provided robust evidence supporting the benefits of chronotherapy in enhancing the efficacy and reducing the toxicity of cancer treatments. For instance, research using mouse models has shown that administering oxaliplatin and 5-FU according to specific circadian rhythms leads to enhanced antitumor effects and lower gastrointestinal toxicity [61].

Clinical trials have further validated the potential of chronotherapy in cancer treatment [62, 63]. The landmark Cancer Chronotherapy Group of the European Organization for Research and Treatment of Cancer conducted a series of clinical trials investigating the effects of chronomodulated chemotherapy in patients with metastatic colorectal cancer. Studies have shown that DNA repair activities tend to peak during the late afternoon and early evening (around 4 p.m. to 8 p.m.) in human tissues, when normal cells are better equipped to repair chemotherapy-induced damage. In contrast, DNA repair is less active during the late night and early morning hours (12 a.m. to 6 a.m.), leaving cells more vulnerable to DNA damage during this time. Chronomodulated chemotherapy takes advantage of these fluctuations, delivering drugs when cancer cells are most susceptible, while minimizing damage to healthy cells during their peak repair phase. By aligning treatment with the body’s natural repair cycles, chronotherapy optimizes the balance between efficacy and toxicity in cancer treatments [62, 64].

Another notable clinical study explored the chronotherapy of irinotecan and chronomodulated infusions in patients with metastatic colorectal cancer [65, 66]. The results indicated that patients receiving chronotherapy experienced fewer severe side effects and better overall survival compared to those receiving standard chemotherapy [66, 67].

Recent advancements in chronobiology and chronotherapy have led to the development of personalized chronotherapy approaches. Using wearable devices such as Fitbit, Oura Ring, and Apple Watch, along with computational models, researchers can now monitor patients’ circadian rhythms in real time and adjust treatment schedules accordingly. This integration of technology not only enhances the precision of treatment timing but also empowers patients to optimize their health outcomes [64, 68]. This personalized approach aims to optimize treatment efficacy while minimizing adverse effects, paving the way for more individualized and effective cancer therapies.

Chemotherapy, one of the mainstays of cancer treatment, has been extensively studied in the context of circadian rhythms. The timing of chemotherapy administration can significantly alter its therapeutic index by modulating drug toxicity and efficacy. For instance, studies have shown that the anticancer activity of 5-fluorouracil (5-FU) is highly dependent on the timing of administration. Specifically, 5-FU is most effective when administered during the early rest phase, which typically corresponds to 4:00 a.m. to 8:00 a.m. in rodents. Administering the drug during this phase not only enhances its therapeutic efficacy but also minimizes associated toxicity. The authors of these studies determined these times by analyzing the circadian regulation of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU catabolism, which shows peak activity during the early rest phase. This peak in DPD activity helps to metabolize 5-FU more effectively, reducing toxicity. Conversely, when 5-FU is administered during the active phase (corresponding to late afternoon to early evening, around 4:00 p.m. to 8:00 p.m. in rodents), DPD activity is lower, leading to increased toxicity. These findings were confirmed through clinical trials and animal studies that closely monitored the drug’s pharmacokinetics, toxicity levels, and response rates relative to the circadian rhythms of the patients and animal models used [65, 70].

Critical insights

Preclinical and clinical research strongly supports the potential benefits of chronotherapy in cancer treatment by aligning therapeutic schedules with patients’ circadian rhythms [69]. Preclinical studies using murine models have demonstrated that administering chemotherapeutic agents like oxaliplatin 5-FU at specific circadian times can significantly enhance antitumor activity and reduce toxicity [70]. These findings suggest that circadian timing influences drug efficacy through mechanisms involving the differential expression‎ of drug-metabolizing enzymes and DNA repair pathways. Clinical trials, particularly those conducted by the European Cancer Chronotherapy Group, have validated these preclinical results in human patients [63]. Chronomodulated chemotherapy has shown improved treatment outcomes, including higher response rates and prolonged survival in patients with metastatic colorectal cancer. This approach also significantly alleviated severe side effects commonly associated with conventional chemotherapy schedules. Specifically, chronotherapy reduced the incidence of gastrointestinal toxicity, including nausea, vomiting, and diarrhea, which are often severe when chemotherapy drugs are administered at non-optimal times. Additionally, hematological toxicities, such as neutropenia, were less frequent when chemotherapy was timed according to patients’ circadian rhythms. The reduced toxicity was attributed to the synchronization of chemotherapy with the body’s natural repair and detoxification processes, which are circadian-regulated [71]. However, challenges such as variability in patient adherence to treatment schedules and logistical issues in clinical settings highlight the need for further large-scale trials to establish standardized chronotherapy protocols.

The advent of wearable devices and computational models marks a significant advancement in personalized chronotherapy, allowing real-time monitoring of patients’ circadian rhythms to optimize treatment schedules [72]. This personalized approach promises to enhance precision medicine by tailoring treatment plans to individual circadian profiles, thereby maximizing efficacy and minimizing adverse effects. Despite the promise, high costs, accessibility issues, and the need for robust data privacy measures pose challenges. Interdisciplinary collaboration is crucial to integrate these technologies effectively into clinical practice [73]. Continued research is necessary to elucidate the underlying mechanisms of circadian regulation in cancer and develop comprehensive guidelines for chronotherapy. Ultimately, integrating circadian rhythms into cancer treatment regimens holds significant potential for improving therapeutic outcomes and patient quality of life, making it a cornerstone of precision oncology [74].

Chronotherapy: optimizing cancer treatment timingIn-depth investigation of chronotherapy strategies for various types of cancer

Chronotherapy, the strategic timing of cancer treatments to align with the body’s circadian rhythms, has shown promising results in enhancing treatment efficacy and reducing side effects. Different cancers exhibit unique responses to chronotherapy, necessitating tailored approaches.

Breast cancer

In breast cancer, chronotherapy has focused on optimizing the timing of chemotherapy to minimize toxicity and maximize efficacy. Studies in rat models have shown that administering chemotherapy drugs like doxorubicin and cyclophosphamide during the late rest phase or early activity phase can enhance therapeutic outcomes and reduce adverse effects. A study by Jamal et al. demonstrated that evening administration of doxorubicin in rats reduced cardiotoxicity compared to morning administration, likely due to the circadian regulation of cardiac repair mechanisms. This evidence suggests that optimizing the timing of chemotherapy administration based on circadian rhythms can mitigate adverse effects while maintaining or enhancing efficacy [75].

Colorectal cancer

Colorectal cancer has been extensively studied in the context of chronotherapy, with notable success. The efficacy of 5-FU and oxaliplatin, key drugs in colorectal cancer treatment, is significantly influenced by the timing of administration. Chronomodulated infusion schedules that administer these drugs during the early night, when the body’s detoxification processes are most active, have been shown to reduce gastrointestinal toxicity and improve patient outcomes [76]. It has been found that patients receiving chronotherapy with oxaliplatin and 5-FU had higher response rates and longer progression-free survival compared to those receiving conventional timing [77, 78].

Lung cancer

For lung cancer, particularly non-small cell lung cancer (NSCLC), chronotherapy research is emerging but promising. The timing of platinum-based chemotherapies, such as cisplatin and carboplatin, has been explored to mitigate nephrotoxicity and enhance anticancer activity. Studies suggest that administering these drugs during the evening can reduce renal damage due to the circadian regulation of renal function [79]. Additionally, circadian timing of radiotherapy has shown potential in improving treatment outcomes and reducing radiation-induced lung toxicity [80].

The role of circadian biomarkers in personalizing treatment timing for improved outcomes

The personalization of chronotherapy relies heavily on identifying and utilizing circadian biomarkers. These biomarkers can provide insights into an individual’s circadian phase and the optimal timing for administering treatments.

Core clock genes

Genes such as PER1, PER2, CRY1, and BMAL1 are central to the circadian clock and exhibit oscillatory expression‎ patterns. Monitoring the expression‎ levels of these genes in peripheral blood mononuclear cells (PBMCs) or tumor tissues can help determine the optimal timing for treatment. Based on these findings, chemotherapy was administered in alignment with PER2 peak expression‎, resulting in reduced side effects and improved efficacy compared to treatments given at other times of the day. This study demonstrates how the monitoring of clock genes such as PER2 can be leveraged to optimize treatment timing, enhancing therapeutic outcomes by synchronizing interventions with the body’s natural circadian rhythms [81].

Melatonin levels

Melatonin, a hormone regulated by the circadian clock, is often used as a biomarker for circadian phase, with secretion peaking at night and suppressed during the day. Although the referenced study discusses melatonin in its introduction, it does not utilize melatonin measurements to monitor circadian rhythms. Nonetheless, measuring melatonin levels in saliva or blood can offer a non-invasive method to personalize treatment schedules in future studies [82].

Rest-activity patterns

Wearable devices like actigraphy monitors have been used in cancer patients to track their rest-activity cycles continuously. For instance, in a study on patients undergoing chemotherapy for breast cancer, actigraphy data revealed significant circadian disruption, with irregular sleep–wake patterns. By analyzing the data, clinicians were able to adjust chemotherapy administration to align with each patient’s circadian rhythm. For patients whose activity levels peaked in the afternoon, treatment was scheduled during this time, which resulted in improved treatment efficacy and reduced side effects, such as nausea and fatigue. This personalized approach demonstrated how wearable devices can tailor treatment timing based on real-time circadian data [83].

Challenges and considerations in implementing chronotherapy in clinical practice

While chronotherapy holds great promise, its implementation in clinical practice faces several challenges and considerations.

Patient compliance

Adherence to chronotherapy schedules requires patients to follow precise timing for medication intake, which can be challenging. Factors such as work schedules, lifestyle, and individual patient preferences can affect compliance [84]. Educating patients on the importance of timing and providing tools, such as reminders and digital health applications, can improve adherence.

Healthcare system constraints

Implementing chronotherapy within the existing healthcare infrastructure poses logistical challenges. Hospital and clinic schedules are typically not designed to accommodate the precise timing required for chronotherapy. Adjusting these schedules to allow for nocturnal or early morning treatments may require significant changes to staffing and resource allocation [11, 85].

Interindividual variability

The effectiveness of chronotherapy can vary between individuals due to differences in circadian rhythms and genetic makeup. Personalizing treatment schedules based on circadian biomarkers requires additional testing and monitoring, which can increase the complexity and cost of care [86, 87]. Developing standardized protocols for assessing circadian biomarkers and integrating them into clinical workflows is essential for widespread adoption.

Integration with existing therapies

Chronotherapy needs to be seamlessly integrated with other cancer treatments and supportive care measures. Coordination between oncologists, nurses, and other healthcare professionals is crucial to ensure that chronotherapy is effectively combined with surgery, immunotherapy, and other treatment modalities [88].

In conclusion, chronotherapy represents a significant advancement in the personalized treatment of cancer. By aligning treatment schedules with the body’s biological rhythms, chronotherapy can enhance drug efficacy, reduce toxicity, and improve patient outcomes. However, successful implementation requires addressing challenges related to patient compliance, healthcare system logistics, and interindividual variability. Continued research and development of chronotherapy strategies, along with advancements in circadian biomarker identification, will pave the way for more effective and personalized cancer therapies.

Circadian rhythms and immunotherapyExamination of the interplay between circadian rhythms and the immune system’s role in cancer

The immune system plays a crucial role in the body’s defense against cancer, and its functions are intricately regulated by circadian rhythms [89]. The circadian clock orchestrates the timing of immune responses, influencing the trafficking, proliferation, and function of immune cells [90]. Key components of the immune system, including natural killer (NK) cells, T cells, and macrophages, exhibit circadian variations in their activity and cytokine production, which can affect their capacity to recognize and eliminate cancer cells [91].

At the molecular level, clock genes such as BMAL1, CLOCK, PER, and CRY modulate the expression‎ of genes involved in immune responses. For example, BMAL1 regulates the rhythmic expression‎ of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), cytokines that play pivotal roles in inflammation and cancer progression [92, 93]. Disruption of circadian rhythms, whether due to genetic alterations or environmental factors, can impair immune function and contribute to an increased risk of cancer [94].

Moreover, the tumor microenvironment (TME) is influenced by circadian rhythms. The TME consists of various cell types, including immune cells, fibroblasts, and endothelial cells, which interact dynamically to support tumor growth and metastasis. Circadian regulation of immune cell infiltration and cytokine production within the TME can impact tumor progression and the efficacy of immunotherapies [95]. Understanding the interplay between circadian rhythms and the immune system is essential for developing strategies to enhance anti-tumor immunity.

The potential for optimizing the timing of immunotherapies, such as checkpoint inhibitors, to enhance anti-tumor immunity

Immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, has revolutionized cancer treatment by harnessing the body’s immune system to target and destroy cancer cells. The efficacy of ICIs, however, can vary significantly among patients, and optimizing the timing of their administration based on circadian rhythms offers a promising strategy to enhance their therapeutic effects [96].

Circadian rhythms influence the expression‎ of immune checkpoints and the activity of effector immune cells. For instance, the expression‎ of PD-1 on T cells and PD-L1 on tumor cells exhibits circadian oscillations, which can affect the sensitivity of tumors to ICIs [97]. Administering ICIs at times when PD-1/PD-L1 interactions are minimal may enhance T cell-mediated anti-tumor responses [97].

Preclinical studies have provided evidence supporting the timing of immunotherapy to circadian rhythms. For example, a study by Loo et al. [98] demonstrated that the efficacy of anti-PD-1 therapy in a mouse model of melanoma was significantly enhanced when administered during the early active phase compared to the rest phase. This timing optimization was associated with increased T cell infiltration and cytokine production within the tumor. Disruption of circadian rhythms, such as through irregular sleep patterns or shift work, has been linked to an increased risk of various cancers, including breast, colorectal, and prostate cancers. The two-process model of sleep, which includes homeostatic sleep drive and circadian rhythms, highlights how these disruptions can lead to impaired DNA repair, dysregulation of cell cycle control, and chronic inflammation, all of which can promote tumorigenesis. For instance, circadian disruption can lead to reduced expression‎ of tumor suppressor genes and increased activity of oncogenes, creating a more favorable environment for cancer development [98].

Furthermore, circadian regulation of the TME, including the rhythmic production of immunosuppressive factors and the recruitment of regulatory T cells (Tregs), can impact the effectiveness of immunotherapies [24]. By aligning the administration of ICIs with periods of reduced immunosuppressive activity, it may be possible to overcome resistance mechanisms and enhance anti-tumor immunity.

Emerging research and clinical trials investigating circadian timing in immunotherapy administration

Emerging research and clinical trials are beginning to explore the potential of circadian timing in the administration of immunotherapies. These studies aim to determine the optimal timing for immunotherapy administration to maximize efficacy and minimize adverse effects.

One such clinical trial is investigating the impact of circadian timing on the efficacy of anti-PD-1 therapy in patients with advanced melanoma [97, 99]. This trial aims to compare the outcomes of patients receiving ICIs during the early active phase versus the rest phase, with the hypothesis that timing optimization will enhance treatment responses and reduce immune-related adverse events.

Additionally, research is focusing on the development of biomarkers to guide the timing of immunotherapy. For example, the expression‎ patterns of clock genes and immune checkpoints in tumor tissues and peripheral blood mononuclear cells (PBMCs) are being studied to identify potential markers that can predict the optimal timing for ICI administration [100].

The integration of wearable technology and digital health tools to monitor patients’ circadian rhythms in real-time is also being explored. These tools can provide personalized insights into patients’ circadian phases and help tailor immunotherapy schedules to align with their biological rhythms [69].

Despite the promising potential of chronotherapy in immunotherapy, several challenges remain. Patient adherence to precisely timed treatment schedules can be difficult to achieve, and the variability in individual circadian rhythms requires personalized approaches [101]. Additionally, healthcare system constraints, such as the need for flexible treatment schedules and coordination among healthcare providers, pose logistical challenges [102].

In conclusion, the interplay between circadian rhythms and the immune system offers a novel avenue for optimizing immunotherapy in cancer treatment. By aligning the administration of ICIs with the body’s biological clock, it is possible to enhance anti-tumor immunity and improve patient outcomes. Ongoing research and clinical trials will provide valuable insights into the feasibility and efficacy of this approach, paving the way for more personalized and effective cancer therapies.

Critical opinion: the role of chronotherapy in cancer treatment

The use of immunotherapy ICIs, particularly the anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, has transformed cancer treatment by leveraging the immune system to specifically target and eliminate cancer cells [103, 104]. However, the efficacy of ICIs varies widely among patients, suggesting a need for optimized administration strategies. One promising approach involves aligning the timing of ICI administration with patients’ circadian rhythms [84]. Circadian rhythms influence the expression‎ of immune checkpoints and the activity of effector immune cells, including T cells and tumor cells. For instance, PD-1 and PD-L1 expression‎ exhibit circadian oscillations, impacting the sensitivity of tumors to ICIs. Administering ICIs when PD-1/PD-L1 interactions are at their lowest could potentially enhance T cell-mediated anti-tumor responses [97, 105]. Preclinical studies have shown that timing immunotherapy to coincide with optimal circadian phases enhances efficacy, evidenced by increased T cell infiltration and cytokine production within tumors [106].

Emerging research and clinical trials are exploring the potential of circadian timing to improve the efficacy and reduce the side effects of immunotherapies. These studies aim to identify the optimal times for ICI administration, guided by circadian biomarkers such as clock gene expression‎ and immune checkpoint patterns. Wearable technology and digital health tools are facilitating real-time monitoring of patients’ circadian rhythms, enabling personalized immunotherapy schedules [107, 108]. Despite the promise of this approach, challenges remain, including ensuring patient adherence to timed treatment regimens and addressing the variability in individual circadian rhythms [109]. Additionally, healthcare systems must adapt to support flexible scheduling and coordination among providers. Overall, aligning immunotherapy with circadian rhythms offers a novel strategy to enhance anti-tumor immunity, and ongoing research is critical to validate and refine this approach, potentially leading to more effective and personalized cancer treatments [110].

The role of lifestyle interventions and chronotherapy in modulating circadian rhythmsInfluence of lifestyle factors on circadian rhythms

Circadian rhythms are endogenously generated cycles that orchestrate a wide array of physiological processes, aligning them with the 24-h day-night cycle. Various lifestyle factors, including sleep patterns, diet, and physical activity, profoundly influence these rhythms.

Sleep

It is a primary regulator of circadian rhythms. The timing, duration, and quality of sleep are critical for maintaining the synchronization of the circadian clock [111]. Irregular sleep patterns, such as those caused by shift work or social jetlag [social jetlag refers to the mismatch between an individual’s internal biological clock (circadian rhythm) and their socially imposed schedule. It commonly occurs when people follow different sleep patterns on workdays compared to their days off, leading to irregular sleep cycles], can lead to circadian misalignment, which has been linked to numerous health issues, including an increased risk of cancer [112]. Proper sleep hygiene, which includes maintaining a regular sleep schedule, creating a conducive sleep environment, and minimizing exposure to artificial light at night, is essential for supporting circadian health [113, 114].

Diet

Nutritional intake and meal timing also play significant roles in modulating circadian rhythms. The timing of food intake can influence the peripheral clocks located in metabolic tissues such as the liver, pancreas, and adipose tissue [37, 115]. Irregular eating patterns, such as late-night snacking or irregular meal timing, can disrupt these peripheral clocks and lead to metabolic disturbances. Time-restricted feeding, where food intake is limited to a specific window during the day, has been shown to enhance circadian alignment and improve metabolic health [116].

Physical activity

Regular physical activity is another crucial factor in maintaining circadian rhythm integrity. Exercise can act as a zeitgeber, or time cue, that helps reset and synchronize circadian clocks [4]. The timing of exercise is important; morning exercise has been found to advance the circadian phase, while evening exercise can delay it. Incorporating consistent, appropriately timed physical activity can thus support circadian alignment and overall health [117].

Recommendations for supporting circadian health through lifestyle modifications

Lifestyle modifications that support circadian health have the potential to enhance the effectiveness of cancer treatments and improve patient outcomes [69]. The following recommendations are based on recent evidence and aim to optimize circadian rhythms through practical lifestyle changes:

Sleep hygiene

Maintaining a consistent sleep schedule is paramount for regulating circadian rhythms. Research shows that irregular sleep patterns can disrupt the body’s internal clock, leading to negative health outcomes, including increased susceptibility to metabolic disorders and mood disturbances. Patients should be encouraged to go to bed and wake up at the same times every day, even on weekends, to reinforce a stable circadian rhythm. A study by Haus and Smolensky found that participants who maintained regular sleep–wake times had more stable circadian patterns and improved metabolic health compared to those with variable sleep schedules [18, 118]. Reducing exposure to blue light from screens at least an hour before bedtime and creating a dark, quiet, and cool sleep environment can also improve sleep quality and duration [119].

Time-restricted feeding: time-restricted feeding

Implementing time-restricted feeding (TRF) can help synchronize peripheral clocks with the central circadian clock. This approach involves consuming all meals within a 10–12 h window during the day and fasting for the remaining hours. Research has demonstrated that TRF can shift the phase of circadian rhythms, aligning metabolic processes with feeding times. For instance, Pan et al. highlight that TRF not only influences metabolic health but also impacts the synchronization of circadian rhythms across various physiological processes. The study indicates that TRF can improve glucose metabolism and insulin sensitivity, suggesting a direct impact on circadian regulation of metabolism. Additionally, TRF has been associated with reduced inflammation and oxidative stress, potentially enhancing the efficacy of cancer treatments. By aligning feeding patterns with natural circadian rhythms, TRF may improve metabolic health markers, decrease inflammation, and create a more favorable environment for therapeutic interventions [120].

Regular physical activity

Encouraging regular physical activity is crucial for maintaining circadian rhythm integrity [121]. Patients should aim for at least 150 min of moderate-intensity exercise per week, as recommended by health guidelines. The timing of exercise should be considered, with morning or early afternoon being optimal for supporting circadian alignment. Avoiding intense exercise close to bedtime is also recommended to prevent disruptions to sleep. Regular physical activity has been shown to influence the expression‎ of clock genes, thereby reinforcing circadian rhythms [117].

Light exposure

Light is the most potent external cue for regulating circadian rhythms. Research highlights that exposure to natural light, particularly in the morning, is essential for setting the circadian clock. Tähkämö et al. note that morning light exposure can advance the circadian phase, enhancing alertness and overall well-being. Conversely, reducing exposure to artificial light, especially blue light emitted by screens in the evening, is critical for preventing delays in circadian timing. This review also emphasizes that evening light exposure is associated with disrupted melatonin secretion and impaired sleep quality, which can further misalign circadian rhythms. Therefore, patients should be encouraged to maximize their exposure to natural light during the day while minimizing artificial light exposure at night to support optimal circadian function [122].

Chronotherapy as an adjuvant therapy in cancer care

Circadian rhythm-based interventions hold promise as adjuvant therapies in cancer care, potentially enhancing the efficacy of conventional treatments and improving patient quality of life.

Chronotherapy implementation

Chronotherapy involves timing the administration of cancer treatments to align with the patient’s circadian rhythms, optimizing treatment outcomes. Research has demonstrated that administering chemotherapy at specific times of the day—when cancer cells are most vulnerable and normal cells are least susceptible to damage—can enhance the therapeutic index of the drugs. For example, a study by Maughan et al. [144] showed that patients with colorectal cancer experienced improved response rates and reduced side effects when treated in alignment with their circadian rhythms compared to those receiving treatment at conventional times. Additionally, studies have indicated that circadian biomarkers, such as melatonin levels and clock gene expression‎, can effectively guide the optimal timing of treatment. For instance, another study found that higher melatonin levels correlate with improved outcomes in patients receiving chronomodulated chemotherapy, suggesting that incorporating these biomarkers can further refine treatment schedules and enhance patient care [123–125].

Melatonin supplementation

Melatonin, a hormone regulated by the circadian clock, has oncostatic properties and can enhance the immune response against cancer cells [125]. Melatonin supplementation has been studied as an adjuvant therapy in cancer care, with evidence suggesting that it can improve the efficacy of chemotherapy and radiotherapy while reducing their side effects [126]. Its role in synchronizing circadian rhythms further supports its potential benefits in cancer treatment.

Behavioral interventions

Behavioral interventions that promote circadian health, such as cognitive-behavioral therapy for insomnia (CBT-I), can improve sleep quality and support overall circadian alignment. Better sleep can enhance immune function, reduce stress, and improve the body’s ability to respond to cancer treatments [127]. Integrating behavioral interventions into cancer care can thus provide holistic support for patients.

Phototherapy

Phototherapy, or light therapy, involves exposure to specific wavelengths of light to regulate circadian rhythms. This intervention can be particularly beneficial for cancer patients experiencing circadian disruption due to treatment schedules or hospital environments. Morning bright light therapy has been shown to improve sleep, mood, and overall circadian alignment, potentially enhancing treatment tolerance and efficacy [128].

In conclusion, lifestyle interventions that support circadian health offer significant potential for improving cancer treatment outcomes. By aligning sleep, diet, physical activity, and light exposure with the body’s natural rhythms, these interventions can enhance the effectiveness of conventional cancer therapies and improve patient well-being. Further research and clinical trials are needed to fully elucidate the mechanisms and optimize the implementation of circadian rhythm-based interventions in cancer care.

Future directions in circadian rhythm research and cancer therapyAdvancements in technologies and approaches for studying circadian rhythms in cancer

The study of circadian rhythms in cancer has advanced significantly with the advent of cutting-edge technologies and innovative approaches. Wearable devices, such as actigraphy monitors and smartwatches, are now commonly used to collect continuous data on sleep patterns, physical activity, and light exposure [129]. These devices provide real-time insights into an individual’s circadian rhythms, allowing for the identification of disruptions and the development of personalized interventions [130].

Omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have revolutionized our understanding of circadian biology. These high-throughput approaches enable comprehensive profiling of circadian gene expression‎ and metabolic pathways in cancer cells and tissues. For instance, RNA sequencing (RNA-seq) can reveal the temporal expression‎ patterns of circadian genes and their regulatory networks in tumors, offering insights into how circadian disruption contributes to cancer progression [93]. Proteomics and metabolomics further elucidate the impact of circadian rhythms on cellular metabolism and protein function, providing a holistic view of the circadian landscape in cancer [131].

Advanced imaging techniques, such as bioluminescence and fluorescence resonance energy transfer (FRET), have also been employed to study circadian rhythms in living cells and organisms [132]. These technologies enable the visualization of circadian clock proteins and their interactions in real time, allowing researchers to dissect the molecular mechanisms underlying circadian regulation in cancer [133].

Integration of circadian rhythm monitoring into personalized cancer therapy plans

Integrating circadian rhythm monitoring into personalized cancer therapy plans holds significant potential for improving treatment outcomes. By continuously monitoring patients’ circadian rhythms using wearable devices, clinicians can tailor treatment schedules to align with the patient’s biological clock. This approach, known as chronotherapy, optimizes the timing of cancer treatments, enhancing their efficacy and minimizing adverse effects [69].

Circadian rhythm monitoring can also inform the timing of other interventions, such as sleep hygiene practices, dietary modifications, and physical activity, to support overall circadian health. For example, time-restricted feeding and regular physical activity can be scheduled to reinforce circadian alignment, potentially improving the patient’s response to cancer therapy [134].

Moreover, the integration of circadian biomarkers, such as melatonin levels and clock gene expression‎, into clinical practice can guide personalized treatment plans. These biomarkers provide objective measures of circadian phase and can be used to adjust treatment timing accordingly [135]. Personalized chronotherapy based on circadian monitoring and biomarkers represents a promising strategy for enhancing the precision and effectiveness of cancer treatment.

Future research needs and the potential for new discoveries in circadian biology

Despite significant advancements in circadian rhythm research, several key areas require further exploration to maximize its potential in cancer therapy. In-depth mechanistic studies are needed to understand the complex interactions between circadian disruption and cancer biology, including its influence on tumorigenesis, metastasis, and treatment resistance at molecular and cellular levels [136]. Large-scale clinical trials are essential to validate the efficacy of chronotherapy and circadian-based interventions across diverse patient populations, with attention not only to treatment outcomes but also to patient quality of life and adherence to circadian interventions [109].

Furthering progress in this field also depends on interdisciplinary research, bringing together chronobiologists, oncologists, and data scientists to leverage big data analytics and machine learning. This collaboration can uncover novel circadian biomarkers and optimize treatment schedules based on individual circadian profiles [137, 138]. Additionally, translational research should focus on developing practical tools and protocols for implementing circadian-based interventions in clinical settings, including designing wearable devices for monitoring, creating standardized guidelines for circadian health, and educating healthcare providers on the principles of chronotherapy [139, 140].

Integrating circadian rhythm research into cancer therapy holds transformative potential. Continued investigation and clinical validation are crucial for fully realizing the benefits of circadian-based interventions, ultimately improving cancer treatment outcomes and patient well-being.

ConclusionSummarization of the importance of circadian rhythms in cancer development and treatment

Circadian rhythms, the intrinsic 24-h cycles governing various physiological processes, play a critical role in maintaining homeostasis and health. Disruption of these rhythms has been increasingly recognized as a significant factor in cancer development and progression. The circadian clock regulates cell cycle progression, DNA repair, metabolism, and immune function, all of which are pivotal in tumorigenesis [131]. Aberrations in circadian regulation can lead to uncontrolled cell proliferation, reduced efficiency in DNA repair, metabolic dysregulation, and impaired immune responses, thereby facilitating cancer initiation and growth [141].

Recent studies have underscored the impact of circadian disruption on cancer risk. For example, shift work and exposure to light at night, which disturb circadian rhythms, have been linked to higher incidences of breast, prostate, and colorectal cancers [142]. These findings highlight the need to consider circadian health in cancer prevention strategies.

In cancer treatment, circadian rhythms influence the pharmacokinetics and pharmacodynamics of anticancer therapies. The timing of drug administration can significantly affect drug absorption, metabolism, efficacy, and toxicity [143]. Circadian biology provides a framework for optimizing cancer therapies, ensuring that treatments are administered at times when they are most effective and least toxic.

Reflection on the potential of chronotherapy to enhance the efficacy and tolerability of cancer treatments

Chronotherapy, which involves aligning treatment schedules with the patient’s circadian rhythms, offers a promising approach to enhance the efficacy and tolerability of cancer treatments. By administering therapies at biologically optimal times, chronotherapy can maximize therapeutic benefits while minimizing adverse effects.

Clinical studies have demonstrated the advantages of chronotherapy in various cancers [16]. For instance, administering chemotherapy at specific times of the day has been shown to improve treatment outcomes and reduce toxicity in colorectal cancer patients [144]. Similarly, the timing of radiotherapy has been found to influence its effectiveness and the extent of side effects [145], with evidence suggesting that treatments administered at certain times can enhance tumor control and reduce damage to healthy tissues [146].

The integration of circadian biomarkers, such as clock gene expression‎ and melatonin levels, into clinical practice can further refine chronotherapy strategies [147]. These biomarkers can provide insights into an individual’s circadian phase, allowing for personalized treatment schedules tailored to each patient’s biological rhythms [69]. Wearable devices and mobile health technologies are emerging as valuable tools for monitoring circadian rhythms in real-time, facilitating the implementation of personalized chronotherapy [148].

Chronotherapy also holds potential in combination with immunotherapy. The timing of immune checkpoint inhibitors and other immunotherapeutic agents can be optimized to align with the circadian regulation of immune responses, potentially enhancing anti-tumor immunity and improving patient outcomes [110]. Emerging evidence suggests that circadian rhythms influence the expression‎ of immune checkpoints and the activity of effector immune cells, providing a rationale for time-based administration of immunotherapies [149].

A call to action for further research, interdisciplinary collaboration, and clinical trial development

To fully harness the potential of circadian rhythm-based interventions in oncology, further research and interdisciplinary collaboration are essential. There is a critical need for mechanistic studies to elucidate the complex interactions between circadian rhythms and cancer biology. Understanding the molecular pathways through which circadian disruption influences tumorigenesis, metastasis, and treatment resistance will inform the development of targeted chronotherapy strategies [150].

Large-scale clinical trials are necessary to validate the efficacy of chronotherapy in diverse cancer populations [93]. These trials should not only eval‎uate treatment outcomes but also consider patient quality of life, adherence to chronotherapy schedules, and long-term benefits [93]. Additionally, research should explore the integration of circadian biomarkers into clinical practice, developing standardized protocols for their assessment and use in guiding treatment timing [151].

Interdisciplinary collaboration between chronobiologists, oncologists, data scientists, and healthcare providers is crucial for advancing the field of circadian oncology. Collaborative efforts can leverage big data analytics and machine learning to uncover novel circadian biomarkers, optimize treatment schedules, and develop personalized chronotherapy plans [69]. Training healthcare providers on the principles of circadian biology and chronotherapy is also vital for translating research findings into clinical practice [69].

The potential of circadian rhythm-based interventions extends beyond cancer treatment. Lifestyle interventions that support circadian health, such as maintaining regular sleep patterns, time-restricted feeding, and regular physical activity, can be integrated into cancer care plans to enhance overall well-being and treatment efficacy [69]. Developing comprehensive care models that incorporate these interventions alongside conventional therapies will provide holistic support for cancer patients.

In conclusion, the integration of circadian rhythms into cancer therapy represents a paradigm shift in oncology. Chronotherapy has the potential to enhance the efficacy and tolerability of cancer treatments, improving patient outcomes and quality of life. Continued research, interdisciplinary collaboration, and clinical trial development are essential to fully realize the benefits of circadian rhythm-based interventions. By embracing the principles of circadian biology, the oncology community can advance towards more effective, personalized, and holistic cancer care.

Author contributions

M.T., S.A.R., A.A.A., I.G.F., H.A.N., I.H.A., A.A.J., M.R., D.P., M.A.K, S.P. wrote the main manuscript text and M.T., S.A.R., A.A.A., I.G.F. prepared the figures. Y.E.T. revised the manuscript, figures and references. All authors reviewed the manuscript.

Funding

The authors did not receive any funding for this work.

Data availability

No datasets were generated or analysed during the current study.

DeclarationsCompeting interests

The authors declare no competing interests.

Footnotes

Publisher's Note

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