케톤혁명 4. 케톤식 효과를 높이는 방법

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beyond reason

케톤혁명 4. 케톤식 효과를 높이는 방법

01. 암세포의 약제내성과 당질내성

약재내성은 암세포가 항암약물을 적으로 간주하고 토해내는 현상을 말함. 이러한 약재내성을 역이용하면 암을 효과적으로 제거할 수 있음. 극단적인 탄수화물 금지식을 지속하면 암세포는 굶주린 상황에 놓임. 이때 항암제를 투여하고 그날만 환자는 탄수화물 80-120mg을 섭취함. 그러면 굶주린 암세포는 포도당을 흡수하면서 혈중 항암제도 함께 흡수하게 됨.

암세포는 항암제를 토해내는  습성을 가지고 있고 그렇게 하기 위해서는 포도당 에너지가 필요함. 그래서 다시 극단적인 탄수화물 금지식사를 하면 암세포 제거가 쉬워짐. 

암세포의 당질내성

암세포의 생존전략 중 하나가 바로 '당질내성'임. 말 그대로 암에 탄수화물 제한에 대한 내성이 생기는 것임. 암치료에서 해결해야 할 장벽임. 

젖산을 에너지로 쓰는 암세포

암세포 중에는 젖산을 에너지원으로 살아가는 암세포가 있음. 젖산이 증가하면 암세포 주위환경은 산성화(젖산혈증)가 촉진되어 정상세포에도 큰 스트레스를 줌. 그래서 케톤체가 많아지면 정상세포는 에너지를 충분히 받고 암세포는 철저하게 굶길 수 있음. 

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Karen G. de la Cruz-López^1,2,3, Leonardo Josué Castro-Muñoz^1,2, Diego O. Reyes-Hernández^4,5, Alejandro García-Carrancá^2,3 and Joaquín Manzo-Merino^2,5,6*

• ¹Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
• ²Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, México/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
• ³Laboratory of Virus and Cancer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
• ⁴Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Maestría en Investigación Clínica Experimental, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
• ⁵Biological Cancer Causing Agents Group, Instituto Nacional de Cancerología, Mexico City, Mexico
• ⁶Cátedras CONACyT-Instituto Nacional de Cancerología, Mexico City, Mexico

Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as “Warburg effect or aerobic glycolysis.” As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

암은 암관련 섬유모세포(cancer associated fibroblast)를 자신의 편으로 만듬. 암관련 섬유모세포는 엄밀히 말하면 아직 암세포는 아니지만 암세포의 명령에 따라 젖산을 만들고 그것을 암세포에 제공하는 암환경을 만듬. 

Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance

• Micol Eleonora Fiori, 
• Simone Di Franco, 
• Lidia Villanova, 
• Paola Bianca, 
• Giorgio Stassi & 
• Ruggero De Maria 

Molecular Cancer volume 18, Article number: 70 (2019) Cite this article

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Abstract

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. 

Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

케톤체를 먹는 암세포

최신 연구에 따르면 포도당 공급이 끊기면 암세포의 70%는 소멸하지만 나머지 30%는 케톤체에 의지하여 에너지를 만듬. 즉 암세포는 체내 환경이 변하면 자신의 체질도 바꾸어 본레는 천적인 케톤체마저도 영양소로 삼음. 특히 암관련 섬유모세포는 정상세포임에도 이런 상황이 되면 암세포에 케톤체를 영양원으로 제공하거나 면역세포를 무력화시키는 등 암의 생존활동에 가담함.  

- 논문 못찾음!!

또한 면역세포 중에는 NK세포나 CTL세포라는 암을 공격하는 세포로부터 암세포를 지켜주는 세포가 존재함. 이를 '제어성 T세포'라고 함. 

Cancer Cell

Perspective

Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies

Roberta Zappasodi,1,2 Taha Merghoub,1,2,3,* and Jedd D. Wolchok1,2,3,4,*
1Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 2Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
4Weill Cornell Medicine, New York, NY 10065, USA
*Correspondence: merghout@mskcc.org (T.M.), wolchokj@mskcc.org (J.D.W.)
https://doi.org/10.1016/j.ccell.2018.03.005

Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Here, we review functional roles of immune checkpoints and molecular determinants of checkpoint-blockade clinical activity. Limited-size T cell-infiltrated tumors, differing substantially from ‘‘self,’’ generally respond to checkpoint blockade. Therefore, we propose that reducing tumor burden and increasing tumor immunogenicity are key factors to improve immunotherapy. Lastly, we outline criteria to select proper immunotherapy combination partners and highlight the importance of activity biomarkers for timely treatment optimization. 

스타틴의 항암효과

스타틴은 '아토르바스타틴칼슘수화물'이 주성분인 콜레스테롤혈증 치료약인데 당질내성을 가진 암세포가 젖산이나 케톤체를 영양원으로 삼으려하면 그 흡수구를 막아줌

즉 스타틴은 암세포의 포도당대사 경로에서 케톤체로 전환되어도 암의 영양섭취 경로를 차단함. 

또한 스타틴 제제는 케톤체처럼 항암제의 약제내성을 해소함. 

스타틴과 우방자 추출물을 함께 마시면 췌장암 효과

암세포의 자가포식현상

암세포가 탐욕스럽다는 것을 뒷받침하는 예로 암세포의 자가포식현상을 들 수 있음. 자가포식 현상이란 자신을 먹는다는 뜻으로 본래는 잉여단백질을 재활용하거나 세포 스스로 영양환경을 정비하는 작용을 말함. 자가포식현상은 정상세포에서 항상 일어나는 생체기능임. 이로 인해 비정상세포의 세포자멸사를 원활하게 유도하고 세포의 암세포 노화를 통제함. 

그런데 암세포 중에서 자가포식현상을 이용하여 세포자멸사를 피하는 경우가 있음. 즉 자가포식현상에 의해 재활용된 잉여 영양분을 다시한번 흡수함으로써 자신의 생존을 확보하고 증식하려 하는 것임. 암세포의 자가 포식 현상을 억제하는 방법이 개발되고 있지만 암을 소멸시키는 대신 일단 암이 생기면 종양형성을 촉진할 위험성도 있으므로 이 방법은 양날의 검임.

암의 자가포식현상을 억제하려면 여분의 영양을 암세포에게 주지 않는 것이 핵심. 정기적인 간헐적 단식과 운동이 필수임

• Review Article
• Published: 13 December 2019

Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients

• Jean M. Mulcahy Levy & 
• Andrew Thorburn 

Cell Death & Differentiation (2019)Cite this article

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• 2 Citations

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Abstract

Autophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors. These activities are thought to be particularly important in cancer where both tumor-promoting and tumor-inhibiting functions of autophagy have been described. Autophagy has also been intricately linked to apoptosis and programmed cell death, and understanding these interactions is becoming increasingly important in improving cancer therapy and patient outcomes. In this review, we consider how recent discoveries about how autophagy manipulation elicits its effects on cancer cell behavior can be leveraged to improve therapeutic responses.

02. 기초체온 향상법

암환자의 체온은 항상 낮음. 암세포가 저체온 상태를 좋아하기 때문임. 

저체온을 형성하는 암세포는 열에 약한 특성을 가지고 있음. 암세포는 언제나 우리 몸 깊은 곳의 체온을 낮추려함. 암세포는 35도체온에서 가장 잘 활성화함. 많은 암 환자의 체온이 36.6-37보다 낮은 35도대까지 떨어지는 것은 우연이 아님. 체온이 낮으면 면역력이 떨어짐. 기초체온 상승은 심부체온 상승의 바로미터이고 면역력 증진의 필수임. 

고주파 온열암(국소온열)

암세포는 41도 이상의 열을 가하면 암세포 증식을 멈추고 급속히 쇠약해짐. 정상세포의 혈관은 열이 가해지면 확장하여 혈류를 늘림으로써 열을 방출함. 하지만 암세포의 혈관은 쉽게 확장되지 못하기 때문에열을 방출하지 못함. 

NF-κB signaling is essential for resistance to heat stress-induced early stage apoptosis in human umbilical vein endothelial cells

Yanan Liu, Gengbiao Zhou, [...], and Lei Su

Additional article information

Abstract

Cell apoptosis induced by heat stress is regulated by a complex signaling network. We previously reported that a p53-dependent pathway is involved. Here, we present evidence that NF-κB signaling plays a crucial role in preventing heat stress-induced early apoptosis. Human umbilical vein endothelial cells (HUVECs) were examined and increased phosphorylation of p65 and IκBα were detected, without IκBα degradation. When NF-κB signaling was inhibited by BAY11-7082, or a small interference RNA (siRNA) targeting p65, a significant increase in cell apoptosis and caspase-3 activity was observed, as well as reduced expression‎ and translocation of HSP27 into the nucleus, an accumulation of reactive oxygen species, and prolonged phosphorylation of mitogen-activated protein kinases (MAPKs). In addition, an association between HSP27 and p65 was identified which may enhance NF-κB activation. When HSP27 was overexpressed, pretreatment of HUVECs with the antioxidant, apocynin, or N-acetyl cysteine, suppressed apoptosis. Similarly, inhibition of JNK and p38 with SP600125 and SB203580, respectively, also suppressed apoptosis, whereas siRNA-mediated HSP27knockdown and treatment with the ERK 1/2 inhibitor PD98059 did otherwise. In conclusion, these findings suggest a novel role for an NF-κB signaling pathway involving HSP27, ROS, and MAPKs that confers a protective effect against heat stress-induced cell apoptosis.

Heatstroke is a life-threatening condition that typically develops following exposure to extended periods of high temperatures. It is characterized by a rapid increase in core temperature to more than 40 °C and multiple organ dysfunction syndrome (MODS)1,2,3. The critical maximum temperature for the human body is between 41.6 °C and 42.0 °C. Previous studies have suggested that apoptosis is a major cause of cell death in heatstroke, and that it can be induced within a few hours4,5. It is hypothesized that endothelial cell activation/injury contributes to the pathophysiology of heat stroke6, and endothelial damage has been detected in heatstroke patients7,8. In addition, recent studies have reported that the acute phase of heat stress induces significant apoptosis in endothelial cells9, and we recently reported that intense heat stress induces early apoptosis via a transcription-independent mitochondrial p53 pathway10. However, the mechanisms mediating cell death in the late phase of heat stress remain unclear.

NF-κB is an important intracellular signaling protein that controls the transcription of several genes involved in cell growth, inflammatory responses, cell survival, and cell apoptosis11. When NF-κB is associated with inhibitory molecules of the IκB family in the cytosol, it is inactive. Correspondingly, most of the inducers that activate NF-κB use a common pathway that involves phosphorylation-induced degradation of IκB proteins. The latter includes the major protein, IκBα, which was the first protein described for this family and is also the most extensively studied IκB protein to date12. Phosphorylation and degradation of IκBα requires phosphorylation of the upstream target, IκB kinase (IKK), which contains two catalytic subunits, IKKα and IKKβ13. Upon release from the NF-κB/IκBα dimer, NF-κB translocates from the cytoplasm into the nucleus to bind DNA and regulate transcription.

암세포는 분열시 유전자를 복제하는 NF-kB라는 인자를 활성화 함. NF-kB는 염증(암세포 증식)을 자극하여 항암치료, 방사선 치료효과를 떨어뜨리는 주범임. 온열암치료로 분비된 HSP(열충격단백질) 70은 면역기능을 높이는 한편 NF-kB의 활성을 억제하여 암세포를 사멸시키는데 중요한 역할을 함. 

즉 HSP 70이 체내에서 얼마나 많이 생성되느냐가 항암온열치료의 중요한 역할임. 

When HSP27 was overexpressed, pretreatment of HUVECs with the antioxidant, apocynin, or N-acetyl cysteine, suppressed apoptosis

 HSP 70을 몸에서 효율적으로 생성해주는 약물이 셀벡스라는 위장약임. 

또한 암세포는 궁지에 몰리면 자신의 항원을 숨기고 면역세포의 공격에서 달아나기도 하는데 HSP70은 암항원을 노출시키는 작용을 함. 이때 NK세포는 암세포를 제거함. 

03. 항암제 부작용에 대처하는 법

활성산소는 '수산화라디칼, 초과산화이온, 과산화수소 등이 있는데 특히 수산화라디칼 Hydroxyl radical (-OH)은 항암치료에서 발생하여 인체에 심각한 부작용을 일으킴. 수산화라디칼은 세포막을 파괴하고 암세포 증식과 전이, 재발을 유발함. 

특히 시스플라틴이라는 항암제는 신장세포의 미토콘드리아를 공격하여 수산화라디칼을 늘림. 그 결과 신장기능 손상을 일으키기도 하므로 주의해야 함. 

수산화라디칼을 제거하는 물질 '비타민 C, E, 케테킨, 폴리페놀, 베타카로틴, 코엔자임 Q10, 플라보노이드 등'이 있음. 항암제 투여로 발생하는 많은 수산화라디칼은 단순히 항산화 비타민, 야채 등을 먹어서 제거되지 않으므로 강력한 항산화 물질이 필요함. 

1) 글루타치온

2) 수소 - 수소가스, 수소물, 수소수 용액주사

네이처 논문(클릭클릭)

Hydrogen Gas in Cancer Treatment

Sai Li, Rongrong Liao, [...], and Kang Peng

Additional article information

Abstract

Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play critical roles in regulating signal transduction and cellular homeostasis. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. Recently, hydrogen gas (formula: H₂) emerges as another GSM which possesses multiple bioactivities, including anti-inflammation, anti-reactive oxygen species, and anti-cancer. Growing evidence has shown that hydrogen gas can either alleviate the side effects caused by conventional chemotherapeutics, or suppress the growth of cancer cells and xenograft tumor, suggesting its broad potent application in clinical therapy. In the current review, we summarize these studies and discuss the underlying mechanisms. The application of hydrogen gas in cancer treatment is still in its nascent stage, further mechanistic study and the development of portable instruments are warranted.

Keywords: hydrogen gas, ROS, inflammation, combination, anti-cancer

특히 수소가스 흡입치료는 폐에 흡수되기 때문에 폐암에 효과가 있음. 수소가스 흡입시간은 한번에 30-60분, 주 3-5회정도면 효과적임. 특히 항암치료를 받은 환자가 항암제 투여일로부터 사흘정도 연속해서수소수를 500ml정도 마시고 3일 연속 수소를 흡입하면 수산화라디칼이 빠르게 제거됨. 

수소분자는 쉽게 용기를 투과하기 때문에 미리 만들어 시판하는 수소소는 실제 표시된 수치보다 농도가 낮을 수 있음. 

저자추천 에코모인터내셔널 수소수

최고 7.0ppm이나 되는 고농도 수수소를 만들수 있음. 

Hydrogen Gas Inhibits Lung Cancer Progression Through Targeting SMC3

Dongchang Wang 1, Lifei Wang 1, Yu Zhang 1, Yunxia Zhao 1, Gang Chen 2

Affiliations expand

• PMID: 29852353
 
• DOI: 10.1016/j.biopha.2018.05.055

Abstract

Lung cancer is one of the most common lethal malignancies in the globe. The patients' prognoses are dim due to its high metastatic potential and drug resistance. Therefore, in the present study, we aim to find a more potent therapeutic approach for lung cancer. We mainly explored the function of hydrogen gas (H2) on cell viability, apoptosis, migration and invasion in lung cancer cell lines A549 and H1975 by CCK-8, flow cytometry, wound healing and transwell assays, respectively. We used RNA-seq, qPCR and western blotting to detect the different expression‎ genes (DEGs) between H2group and control group to find the gene related to chromosome condensation. Besides, we confirmed the structural maintenance of chromosomes 3 (SMC3) and H2 on the progression of lung cancer in vitro and vivo. Results showed that H2 inhibited cell viability, migration and invasion, and catalyzed cell apoptosis and H2 induced A549 and H1975 cells G2/M arrest. Besides, H2 down-regulated the expression‎ of NIBPL, SMC3, SMC5 and SMC6, and also reduced the expression‎ of Cyclin D1, CDK4 and CDK6. H2 translocated the subcellular location of SMC3 during cell division and decreased its stability and increased its ubiquitination in both A549 and H1975 cells. In addition, inhibition of the proliferation, migration and invasion and promotion of the apoptosis of A549 and H1975 cells induced by H2 were all abolished when overexpressed SMC3 in the presence of H2. Animal experimental assay demonstrated that the tumor weight in H2 group was significantly smaller than that in control group, but was bigger than cis-platinum group. The expression‎ of Ki-67, VEGF and SMC3 were decreased when mice were treated with H2 or cis-platinum, especially for cis-platinum. All data suggested that H2 inhibited lung cancer progression through down-regulating SMC3, a regulator for chromosome condensation, which provided a new method for the treatment of lung cancer.

Keywords: Chromosome condensation; Hydrogen gas; Lung cancer; SMC3.

3) 비타민 C

수소수, 수소흡입과 고농도 비타민 C수액을 주입하면 환자의 모든 ORP는 극단적으로 내려감. 

참고) Oxidation-reduction potential 활성산소 양 측정(클릭클릭)

04. 암세포를 죽이는 미토콘드리아

미토콘드리아가 회복되면 암은 회복됨. 미토콘드리아 수에 건강에 좌우됨. 여성이 남성보다 오래사는 이유는 여성의 미토콘드리아 숫자가 많기 때문.  미토콘드리아는 여성에게 많은 적근에 더 많이 분포함. 근육량이 증가하면 온몸의 미토콘드리아 숫자가 증가함. 

기아상태가 미토콘드리아를 늘림

미토콘드리아는 육체가 위기에 놓이면 장수유전자 스위치를 켜서 급격히 증식함. 그 대표적인 예가 공복일때 에너지 보충필요성을 느낀 뇌가 전신의 세포에 미토콘드리아 증식명령을 내림. 그리고 인간의 몸은섭씨 12도의 물에 10분간 담고고 있으면 미토콘드리아 증식 스위치가 켜지는 것도 밝혀짐. 

유산소 운동과 간헐적 단식의 조합은 케톤체 생성과 미토콘드리아 활성을 강력하게 추진함. 뇌는 공복상태가 되거나 추위에 노출되면 온몸에 위험신호를 보냄. 장수유전자를 켜고 미토콘드리아를 늘림. 

간헐적 단식과 운동의 조합법

아침에 MCT오일 15g

11시경 유산소 운동 20분

뇌는 에너지가 부족하다고 판단하여 미토콘드리아를 늘리라는 명령을 내림

케톤체 에너지(지방연소기)를 사용하는 몸은 실제로는 에너지가 부족하지 않음. 뇌의 착각임. 

점심에 GI지수가 낮은 탄수화물(고구마)를 간단히 먹음. 공복시 운동을 한뒤 탄수화물을 섭취하는 것은 기아 상태에 빠진 정상세포에 탄수화물이 우선적으로 흡수되어 암세포에는 흡수되지 못함. 

참고)

조코비치의 식단

2010년 조코비티는 글루텐과 유제품 알레르기가 있다는 사실을 알게됨. 그리고 케톤식단을 바꾸고 조코비치는 세계 최고의 테니스 선수로 거듭남. 

일주일 항암케톤식단

아침식사는 채소중심

점심은 단백질을 충분히 섭취

저녁식사는 80%정도로 섭취

아마씨유와 MCT오일은 식사할때 반드시 섭취

아마씨유 하루 섭취량은 30g. 15g씩 하루 2회 섭취

MCT오일은 하루 몇번 나누어 60-80g섭취