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The Warburg "effect" Is, In Fact, A Direct Cause Of Cancer

Discussion in 'Scientific Studies' started by haidut, Oct 4, 2018.

  1. OP
    haidut

    haidut Member

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    They basically confirmed the primary role of the Warburg "effect" in cancer - i.e. in line with the study in the original post above they found that the Warburg "effect" in fact causes cancer cells to grow. It is kind of sad they call this "trailblazing" since the role of lactate as the most potent endogenous VEGF promoter has been known for decades. That why VEGF blocking drugs are one of the main therapies for cancer.

    "...Using the results of FBA in models of populations of cells in the form of solid tumors, the group confirmed that the Warburg effect provides a growth advantage for the tumor, but that glutamine addiction does not benefit tumor cells’ growth. “We show that it’s not helpful [for the tumor] to be glutamine-addicted,” Stroock said. “The community will have to find other ways in which glutamine is important.” Stroock’s team also offered insights into the relationship between healthy cells and tumor cells under the reverse Warburg effect, which allows more oxygen to penetrate the cancerous mass in resource-limited microenvironments. Stroock said the group’s work, while opening doors to future study, also confirms a nearly 100-year-old theory. “It puts this ancient hypothesis on more solid footing,” he said, “and we now know more quantitatively … how cancer cells use this Warburg mechanism.”
     
  2. Mito

    Mito Member

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    He was just on a podcast ( https://peterattiamd.com/tomseyfried/) talking about cancer as a mitochondrial disease. Many of the things he talked about are very similar to Peat's view.

    A few Seyfried quotes from the podcast:

    (regarding cellular respiration)"...enables all the cells of our or the major of cells in our body to perform this very efficient form of energy production which then frees up the cells to do their sophisticated behaviors, liver cells do what they do, kidney cells, brain cells they all do what they do because they have this very efficient energetic system that's working called respiration."

    "Pete Peterson from John's Hopkins had done a magnificent job in collating all this information and he found that in every kind of a cancer cell no matter what kind it is there was some kind of a defect in the number, structure, or function of the mitochondria and it could vary. So some cancer cells have very few mitochondria but they looked normal very, few of them, other tumor cells clearly have a lot of mitochondria but they look abnormal. So whatever it was it was something to do with an impairment of the respiratory system within the cell, and if the cell can't generate energy through normal respiration, then it has to ferment there is no other way it can get the energy."

    ".....everybody says respiration is normal in cancer cells, and why would they say it's normal, because they started doing cells in culture rather than looking at the tissues themselves, and once you start doing culture work your taking cells from a tissue and separating them and growing them as if they were micro-organisms in the culture dish, well this changes everything, they're no longer connected to each other there growing in some artificial fluid and there doing things that they sometime do sometimes not do in the real world so you make a lot assumptions based on a system that is artifactual.

    Peter Attia asking about genetic mutations and cancer..."And is the idea that the those mutations were acquired"....."in other words the genome is unaffected in some of those cases?" Seyfried's reply: "yes we've done that, we've sequenced the entire genome of five different independently derived cancers from mouse all derived from different origins and we didn't find a single genetic abnormality what we call pathogenic where the mutation would actually have an effect on a function and we didn't find a single one."

    "...so we only know that you don't get cancer if you're mitochondria remain health that's what we know so that's an important because that goes back to the prevention issue, how do you prevent cancer? You prevent cancer by keeping your mitochondria healthy. How do you do that, well you avoid if you can those risk factors mostly from the environment like viral infection, intermittent hypoxia, radiation exposure, carcinogenic exposure all these different things everyone of those things can damage respiration in a population of cells then leading to cancer because we know of no cancer that has normal respiration...."

    Seyfried does however differ from Peat on how to use these ideas to fight an existing cancer. Seyfried is doing clinical studies in Turkey where they use ketogenic diets to minimize glucose and then intermittently use glutamine antagonist to starve the cancer cells and also hyperbaric oxygen. (Clinical trial in Turkey: Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer (Iyikesici et al., 2017) [2:13:15])
     
  3. jondoeuk

    jondoeuk Member

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  4. Mito

    Mito Member

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    Why do you think some studies show blocking Complex I inhibits tumor proliferation?

    “In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiaeNADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.
    Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

    Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
    Highlights
    • A screen identifies complex I inhibitors as highly selective against Pten-null cells
    • Pten-null selectivity is unmatched by common standard of care chemotherapy agents
    • Mitochondria of Pten-null cells easily switch to consuming ATP instead of producing it
    • The complex I inhibitor deguelin can suppress lethal prostate cancer in RapidCaP.
    https://www.cell.com/cell-reports/pdf/S2211-1247(18)30374-7.pdf
     
  5. jondoeuk

    jondoeuk Member

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    Using an MCT1 inhibitor increases mitochondrial metabolism MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy

    In my view you want to target that, MCT4 and at least Complex I https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31806-0 The downside is that Metformin is usually ineffective. So we need better drugs.

    I know AstraZeneca has one MCT1 inhibitor in a clinical trial (NCT01791595) and they are working on a MCT4 inhibitor too. Some early data has been published for the former http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2516
     
  6. OP
    haidut

    haidut Member

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    I don't know but on the flip side even Wikipedia talks about how deficiency of Complex I and a resulting build up of succinate is a known driver of tumor progression.
    Succinic acid - Wikipedia
    "...Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in tumorigenesis.[37][41] Loss-of-function mutations in the genes encoding succinate dehydrogenase, frequently found in hereditary paraganglioma and pheochromocytoma, cause pathological increase in succinate.[31] SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and neuroblastomas.[37] The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit 2-oxogluterate-dependent dioxygenases."
     
  7. LeeLemonoil

    LeeLemonoil Member

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    That's somewhat disturbing to read about succinic acid - I take it it is still a mito-beneficial supplement in moderate doses and when mito-respiration is not impaired by mutations or otherwise?
     
  8. Obi-wan

    Obi-wan Member

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    According to this Pub Med Report Physiological roles of mitochondrial reactive oxygen species

    "Although autophagy has been widely shown to be a survival pathway, under certain circumstances that are not completely understood at this time, autophagy can guide cell death in a process called ‘autophagic cell death.’ This method of controlled cell death is distinct from apoptosis. Some evidence suggests that mROS guide the cell fate decision to induce autophagic cell death. Autophagic cell death is induced by selective degradation of catalase, which leads to vast accumulation of H2O2 and subsequent cell death presumably by nonspecific oxidative damage (Yu et al., 2006). The source of H2O2 appears to be mitochondria, as inhibitors of complex I and complex II can directly induce autophagic cell death by increasing mROS (Chen et al., 2007). Therefore mROS may play dual functions in the context of autophagy – low levels may promote survival by inducing autophagy to allocate intracellular resources under starvation, while high levels may promote controlled autophagic cell death when survival is not possible.
     
  9. LeeLemonoil

    LeeLemonoil Member

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    The olive leaf extract oleuropein exerts protective effects against oxidant-induced cell death, concurrently displaying pro-oxidant activity in hum... - PubMed - NCBI

    The olive leaf extract oleuropein exerts protective effects against oxidant-induced cell death, concurrently displaying pro-oxidant activity in human hepatocarcinoma cells.

    Katsoulieris EN1.
    Author information
    Abstract

    OBJECTIVES:
    Oleuropein (OP), the predominant natural constituent of leaves of the olive tree, exerts anti-inflammatory and antioxidant effects. The purpose of this study was to assess the protective effects of OP under the conditions of paraquat (PQ)-induced oxidative stress in vitro, using the human hepatocarcinoma cell line, HepG2.

    METHODS:
    Cell viability and death were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4',6-diamidino-2-phenylindole-propidium iodide staining, respectively. Superoxide anion and lipid peroxidation levels were evaluated using nitroblue tetrazolium and thiobarbituric acid-reactive substances assays, respectively. Apoptosis was assessed by measuring poly(ADP-ribose) polymerase (PARP) and caspase-3 (Casp-3) cleavage via immunoblotting and immunofluorescence analyses.

    RESULTS:
    PQ induced a decrease in cellular viability by promoting necrosis through a mechanism involving superoxide generation and nuclear translocation of cleaved Casp-3. Co-treatment with OP afforded significant protection against the suppressive effects of PQ, as evident from increased cell viability, reduction of Casp-3 immunofluorescence, and normalization of β-tubulin expression levels. Unexpectedly, these OP-mediated protective effects were associated with increased superoxide and malondialdehyde generation and PARP cleavage.

    DISCUSSION:
    OP protects HepG2 cells against PQ-induced necrosis by suppressing Casp-3 cleavage while concomitantly acting as a pro-oxidant agent. This paradoxical mechanism of action of OP requires further investigation.
     
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