Opportunities in the Metabolic Chaos of Cancer

Abstract

Cancer cells demonstrate the Warburg Effect. They ferment fuel by anaerobic glycolysis despite the presence of oxygen. This remarkable metabolic transformation at the onset of malignancy appears to be an innate adaptation to hypoxia. Cancer cells always continue some oxidative phosphorylation, and will die in a completely anoxic environment, but adapt to a crowded, compressed, and hypermetabolic situation by moving almost entirely to a metabolic phenotype that can operate without oxygen. Fermentation is not just an alternative way to obtain cellular energy – it provides increased biosynthesis of cellular components necessary to maintain exponential tumour growth. Anaerobic glycolysis is also a route to epigenetic alteration of the phenotype. Increased de novo synthesis includes not only structural cellular components, but also signaling molecules such as succinate that interact with both oncogene and tumour suppressor pathways. The mitochondria reprogram the cancer cell genetics to a new fermentative, fetal-like phenotype characterized by symmetrical mitosis. Targeting fermentation by cancer cells appears to have huge potential for healing and preventing cancer. Tumour growth and spread is linearly related to loss of, and damage to cancer cell mitochondria. Restoring mitochondria numbers and polarization, with redirection of cellular bioenergetics back towards oxidative phosphorylation, is possible. This tactic should result in lower rates of disease progression, invasion, metastasis, and relapses, particularly in common and deadly cancers which are grossly fermentative, such as of the breast, pancreas, liver, and colon.

Introduction

Cancer cells demonstrate the Warburg Effect (Koppenol et al 2011, Warburg 1956) – they ferment fuel by anaerobic glycolysis despite the presence of oxygen. This remarkable metabolic transformation at the onset of malignancy appears to be an innate adaptation to hypoxia. Surgeries and traumas create hypoxic zones. The Standard American Diet (SAD) creates a significant net acid residue compared to ancestral diets, reducing cytoplasmic oxygen retention (Frassetto et al 2001, Pizzorno 2012). Cancer cells always continue some oxidative phosphorylation, and will die in a completely anoxic environment, but adapt to a crowded, compressed, and hypermetabolic situation by moving almost entirely to a metabolic phenotype that can operate without oxygen. Reduced perfusion creates relative hypoxia, and the resulting shift to glycolytic metabolism (Fang et al 2008) generates high acid residue, which interacts with the pH gradient and resulting voltage gradient in mitochondria when moving protons necessary for ATP production by oxidative phosphorylation (Lewis et al 2002), reinforcing the adaptation to the hallmark cancer cell dependence on anaerobic glycolysis. Fermentation is not just an alternative way to obtain cellular energy, it provides increased biosynthesis of cellular components necessary to maintain exponential tumour growth and is a route to epigenetic alteration of the phenotype. Increased de novo synthesis includes not only structural cellular components, but also signaling molecules that interact with both oncogene and tumour suppressor pathways (Röhrig and Schulze 2016). The mitochondria reprogram the cancer cell genetics to a new fermentative, fetal-like phenotype (Seyfried 2012, Wallace 2012).

Targeting fermentation by cancer cells appears to have huge potential for healing and preventing cancer (Abdel-Wahab et al 2019, Bucay 2007, Frezza and Gottlieb 2009, Gogvadze et al 2008, Hanahan and Weinberg 2000, Hanahan and Weinberg 2011, Kulawiec et al 2009, Vander Heiden et al 2009, Wallace 2005, Yeung et al 2008). Tumour growth and spread is linearly related to loss of, and damage to, cancer cell mitochondria (Christofferson 2014). The landmark dichloroacetate (DCA) study of 2007 from the University of Alberta showed that restoring the malignant cell mitochondrial membrane potential can spark up oxidative metabolism, and this will arrest tumour growth (Bonnet et al 2007). Restoration of mitochondrial respiration must also influence the retrograde signaling and epigenetic reprogramming of cancer cells. This normalization of cellular bioenergetics should result in lower rates of disease progression, invasion, metastasis, and relapses, particularly in common and deadly cancers which are grossly fermentative, such as of the breast, pancreas, liver, and colon.

Possible Opportunities for Impacting Cancer Cell Metabolism

The number of cells in a given tissue remains constant once in the second trimester of gestation. Normal cells follow a mature growth pattern whereby cells do not reproduce, but if lost, are replaced from stem cells, in a process called asymmetrical mitosis. The stem cell makes a functional replacement differentiated cell, plus a new stem cell for future use. Cancer cells are reprogrammed to behave like the earlier fetal cells, with symmetrical mitosis generating masses of relatively undifferentiated cells. Cancer cells with this unlocked mitotic potential arise from a multitude of factors, such as radiation-induced mutations and DNA damage, toxic exposure such as to heavy metals (e.g. cadmium), or from bioactive chemicals such as pesticides. Inherited defects in DNA repair and other genetic issues account for perhaps 10% of cases. The Standard American Diet (SAD) leads to a dramatic increase in acid load and profound alterations in the sodium-potassium ratio (Frassetto et al 2001, Pizzorno 2013), which alters oxygen capacity of the cytoplasm. Mitochondrial and endoplasmic reticulum nutrient sensors adapt with changes to mitochondrial membrane function (Arnett 2010, De Saedeleer et al 2012, Fang et al 2008, Lemasters and Holmuhamedov 2006, Pizzorno 2012, Robey 2012). Mitochondria are also more sensitive and less able to repair DNA damage from most drugs and toxic substances (Cohen 2010, Darlington 1948). Cancers always have mitochondrial damage (Jurasunas 2006, Okouoyo et al 2004, Singh 2004, Varga et al 2015). The degree to which any cancer grows and spreads has a linear relationship to the number of lost or damaged mitochondria, and the shift to an increasing dependence on fermentation – burning fuel without oxygen (Christofferson 2014). Seyfried (Seyfried 2012, Seyfried et al 2014, Seyfried 2015, Seyfried et al 2017) and others have demonstrated that mitochondria are able to send retrograde signals to the nuclear DNA, reprogramming metabolism (Caino and Altieri 2016, Cerella et al 2015, Hung et al 2010, Ishikawa et al 2008, Jose et al 2011, Kaipparettu et al 2013, Ralph et al 2010, Wallace 2012). While anaerobic glycolysis is distinctly inferior to aerobic metabolism in terms of ATP energy production per molecule of fuel such as glucose, the cancer cells end up with normal amounts of energy by adaptations such as recruiting stromal cells to make ATP, a process called the Reverse Warburg Effect (Feron 2009, Sotgia et al 2011, Sotgia et al 2012).

Accumulation of succinate is a key aspect of metabolic dysregulation in carcinogenesis. This buildup of a Krebs cycle metabolite inhibits several α-ketoglutarate dioxygenases, thereby inducing a pseudohypoxia pathway (Teicher et al 2012), and via hypoxia inducible factors HIFαand HIF β, causes epigenetic reprogramming of genes regulating energy metabolism, angiogenesis and cell survival. Loss of succinate dehydrogenase enzyme (SDH) (aka Complex II) leads to reprogramming of cell metabolism to support glycolysis. Mutations of genes encoding for the succinate dehydrogenase complex are associated with familial paraganglioma, pheo-chromocytoma, renal cell carcinoma, gastrointestinal stromal tumors and, possibly, pituitary adenomas. SDHx-related tumors display the Warburg effect, driven by HIFα, which induces expression of GLUT1 and GLUT3, hexokinase 2, pyruvate kinase variant M2 (PKM2) and lactate dehydrogenase A (LDH-A), thereby stimulating the shift from oxidative phosphorylation to glycolysis. There is an overexpression of LDH-A which converts pyruvate to lactate, thereby recovering the NAD+ needed to maintain glycolysis, critically important for tumor proliferation. Inhibitors of GLUT1, pyruvate dehydrogenase kinase (eg DCA), and pyruvate carboxylase are potential targets for treatment of SDHx-associated tumors (Eijkelenkamp et al 2020). SDHx also triggers the epithelial to mesenchymal transition, cell migration and invasion (Dalla Pozza et al 2020). Anti-inflammatory tumour-associated macrophages (TAMs) secrete cytokine TGF-β that suppresses the transcription factor STAT1, decreasing the production of succinate dehydrogenase (SDH) enzyme in breast cancer cells (Gomez et al 2020). Melatonin may inhibit succinate accumulation (Gu et al 2020).

Central to the shift to a malignant phenotype is the down-regulation of phosphatases that dampen reactions and the up-regulation of kinases that stimulate metabolism and growth. The key metabolic controller pyruvate dehydrogenase kinase (PDK) creates a biochemical bottleneck, with a shift towards fermentation (Luo et al 2011, Pathania et al 2009). Under hypoxic conditions oxidative phosphorylation (OxiPhos) can no longer convert pyruvate to acetyl-CoA via the tricarboxylic acid (TCA) cycle. Anaerobic glycolysis uses lactate dehydrogenase (LDH) pathway to convert pyruvate to lactate, and lactate to pyruvate (da Veiga Moreira et al 2021).

The other hallmark of the malignant cell metabolism is glutaminolysis, the burning of glutamine as a fuel to generate TCA metabolites such as citrate, glutamate, pyruvate, and lactate, for the production of nucleic acids and other important cellular components needed by the cancer cells. For example, citrate can be used to make acetyl-CoA, which is needed to produce de novo lipids. These fatty acids are used structurally, but also as signalling molecules acting on oncogenes and tumour suppressor pathways (Röhrig and Schulze 2016). Normal cells use hexokinase one (HK1 or Hex I) on the mitochondrial membranes to move glucose, but cancer cells also make the unique hexokinase two (HK2 or Hex II) in abundance. HK2 takes ATP and glucose and produces glucose-6-phosphate. This precursor to lactate serves to lock on the throttle of glycolysis. Not only does this shift in biosynthesis of cellular components increase cell proliferation, it inhibits apoptosis, effectively immortalizing the malignant cells (Mathupala et al 2006).

In a landmark study in 2007 at the University of Alberta, it was demonstrated that dichloroacetate (DCA), a simple chlorinated vinegar, could inhibit PDK and shift mitochondria in cancer cells back to oxidative phosphorylation (Bonnet et al 2007). Rather than this pyruvate mimetic (Stockwin et al 2010) “giving the cancer more energy” as might have been imagined, the result was a dramatic decline in cancer growth. Unfortunately, premature hype of DCA (Coghlan 2007) lead to many people being harmed by self-prescribing on DCA obtained over the internet, overdosing (no human dose had been determined), or from using fraudulent or contaminated products. The first controlled human trial of DCA for cancer in 2010 showed significant toxicity to the peripheral nervous system, limiting its utility to brain and neurological cancers, which it rapidly saturates (Michelakis et al 2010). A smattering of published case studies has demonstrated some positive outcomes (Khan 2011, Khan 2012, Khan et al 2014, Khan et al 2017). DCA is highly neurotoxic when taken by mouth (Cornett 1999, Felitsyn 2007, Kaufmann 2006, Stacpoole 1998, Schaefer 2006).

The mechanism of action of DCA: DCA inhibits pyruvate dehydrogenase kinase, triggering an influx of acetyl-CoA into mitochondria. This drives more NADH into complex I. Superoxides that form are converted into hydrogen peroxide by manganese-super oxide dismutase. The H2O2 inhibits proton (H+) efflux, reducing mitochondrial membrane potential Dym, the proton-driving force → ATP. This opens the mitochondrial transition pore (MTP), inhibiting calcium ion entry via voltage-dependent channels. Reduced intra-mitochondrial calcium (Ca++) suppresses a tonic activation of nuclear factor of activated T-lymphocytes (NFAT). NFAT1 is a nuclear transcription activator, similar in action to activator protein 1 (AP-1) and nuclear factor kappa B (NFkB). This reduces Kv1.5 expression, increasing potassium ion K+ efflux, reducing inhibition of caspases, and finally triggering cancer cell apoptosis (Bonnet et al 2007).

Fortunately, there are promising candidates for safer alternatives to DCA, as published in the first peer-reviewed paper on “mitochondrial rescue” as a potential cancer therapy (McKinney 2008), revised and republished in 2011 (McKinney 2011). The most important elements of this mitochondrial rescue protocol were R-alpha lipoic acid (ALA) (Abolhassani et al 2012, Baronzio et al 2012, Dörsam and Fahrer 2016) and thiamine – vitamin B1 (Babaei-Jadidi et al 2003, Comin-Anduix et al 2001). ALA activates pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDK), which results in an increased amount of pyruvate entering the tricarboxylic acid cycle. This drives the mitochondria towards oxidative phosphorylation and away from the Warburg effect anaerobic glycolysis on which cancer cells depend. Adjuncts to support R-ALA in normalizing the functionality of mitochondria include the Co-enzyme Q10 derivative PQQ (pyrroloquinoline quinone), thiamine derivative benfotiamine, acetyl-L-carnitine, grapeseed extract, and quercetin. Dr. Walter Lemmo’s discovery that DCA given by IV route was far less toxic than by mouth (private communication) revealed the potential to use DCA safely on non-neurological cancers. Later it was found that DCA and R-ALA could also be safely ingested by inhalation using a nebulizer (McKinney 2020B, McKinney 2020C). This metabolic approach was tried in many patients with advanced cancer, or cancers not responsive to the standard of care, with some good responses, including in some cases rapid tumor shrinkage. However, these anecdotal reports have yet to be fully tested in controlled studies or published under peer-review.

As well as fixing the damaged mitochondria in the cancer cell, it is also possible to increase the number of mitochondria, known as mitogenesis. One tactic for increasing mitogenesis is to increase intracellular nitric oxide, which can be accomplished with grapeseed extract proanthocyanidins (Vitseva et al 2005). Another mitogenic tactic is to activate adenosine monophosphate kinase (AMPK) (Chaube and Bhat 2016), which we may achieve with aerobic exercise, resveratrol, curcumin, quercetin, metformin, berberine, or green tea EGCG (McKinney 2020B, McKinney 2020C). Mitogenesis will also increase if peroxisome proliferator-activated receptor (PPAR) gamma γ (Jamwal et al 2021) coactivator 1α (PGC-1α) is inhibited with fermented wheat germ extract (FWGE) or red wine. PGC-1α is a transcriptional coactivator of the fusion mediator mitofusin-2, which is modulated by resveratrol. Also potentially effective would be increasing the levels of the “fountain of youth” sirtuin protein SIRT1, an NAD-dependent histone deacetylase, by caloric restriction, resveratrol, quercetin, or exercise (Archer 2013, Shigenaga and Ames 1993).

Another key part of the malignant mitochondrial metabolic puzzle is how to inhibit Hexokinase II (HK2 or Hex II), to further shift away from fermentation (DeWaal et al 2018, Mathupala et al 2006). HK2 binds to mitochondrial porin, redirecting mitochondrial ATP to phosphorylate glucose and driving glycolysis (Wallace 2005). Dr. Davis Lamson, ND, and others such as Israel and Schwarz in France put forward several candidate inhibitors, including hydroxycitrate from Garcinia cambogia (Guais et al 2012, Israel and Schaeffer 1988, Israel and Schwartz 2011, Schwartz et al 2010, Schwartz et al 2012, Schwartz et al 2013, Schwartz et al 2014). Clinical responses to hydroxycitrate have not been robust. In pre-clinical studies, lectins from Solomon’s seal herb (Polygonatum spp.) strongly inhibit HK2 (Wang et al 2011, Zhang et al 2017) and GLUT2 (Wang et al 2018). The target lectins are most abundant in the leaf, explaining why the whole-herb extracts seem to be much more bioactive in oncology than the root extracts commonly used for arthritis. The bioflavonoid quercetin is also a candidate Hex II inhibitor (Graziani 1977). Itraconazole is an antifungal drug that is being repurposed as a Hex II inhibitor (Gu et al 2016).

Another opportunity to intervene in the fermentation phenotype in cancer is how it regulates the highly acidic and toxic lactate output. Lactate can behave as a hypoxia mimetic factor capable of activating transcription factor HIF-1 in normoxic cancer cells, a key step in angiogenesis (Koukourakis et al 2005, Koukourakis et al 2006), and in triggering cancer cells to develop stem cell properties by which they become virulently malignant. Lactate over-production has many negative consequences (Walenta et al 2000, Walenta et al 2004), including reducing tumour antigenicity to dendritic immune cells (Gottfried et al 2006). Cancer cells are distinctly more alkaline on the inside than normal cells of the same type (Hao et al 2018), although the environment right around them is highly acidic (Newell et al 1993). This localized pH stress is an obvious therapeutic target (Huber et al 2017, Martin et al 2012, McCarty and Whitaker 2010, Pilon-Thomas et al 2016) but one that has proven elusive to overcome in practice. Laypeople as well as doctors have assumed from a cursory view of Warburg’s findings that a net alkaline residue diet, and alkaline therapies such as intravenous bicarbonate, will address this problem, but clinical results have been marginal (Martin et al 2012, Wenzel and Daniel 2004). Alkalizing increases patient quality of life but has little to no impact on progression of the disease. Rather than halting lactate production, or neutralizing it in the periphery of the tumour, it may be best to keep it in  the cancer cell. In malignant cells there is a dramatic up-regulation of proton efflux pumps, shifting the acidic lactate from the cancer cell cytoplasm out into the pericellular spaces. This opens up the possibility of killing cancer cells by inhibiting these proton-coupled mono-carboxylate transporters, especially MCT1 and MCT4 (Benjamin et al 2018, Colen et al 2011, Payen et al 2020, Pérez-Escuredo et al 2016, Sun et al 2020). Quercetin appears to be the most promising intervention to address this tactic (Batiha et al 2020, Jones et al 2017, Ikegawa et al 2002).

Ketogenic diets are a relatively new concept in cancer care (Harper and Drewery 2019, Katz and Edelson 2017, McKinney 2020A, McKinney 2020C, Poff et al 2015, Seyfried et al 2009, Winters et al 2017). Very high fat, moderate protein, and very low carbohydrate ketogenic diets take advantage of the ability of normal cell mitochondria to adapt to ketones as fuel, while cancer cell mitochondria cannot do so (Davis 2017, de Cabo and Mattson 2019, Khodabakhshi et al 2020, Lee and Longo 2011, Longo and Fontana 2010). Some possible adjuncts to the ketogenic diet are supplemental ketones such as β-hydroxybutyrate, acetoacetate or 1,3,butane-diol, Metformin, berberine, Poly-MVA™ lipoic acid-palladium complex, hyperbaric oxygen therapy, and vitamin A retinol (Anderson 2018, Stengler and Anderson 2018). Fasting was once a widely used tool for healing, and research is now returning this dietary intervention to the clinical practice. Fasting – near, full, or intermittent – positively influences tolerance of SOC (standard of care) oncology therapies, and increases survival, in part by destressing mitochondria (Lee et al 2010, Lee and Longo 2011, Longo and Fontana 2010, Lv et al 2014, Safdie et al 2009, Simone et al 2018).

Discussion

Cancer cells adopt a phenotype largely dependent on anaerobic glycolysis. The cell is epigenetically reprogrammed to a fetal growth pattern. Since the cell has once undergone a shift from the fetal growth pattern (symmetrical mitosis) to the mature normal cell replacement model (asymmetrical mitosis), it is possible a mechanism exists to move the cancer cell from symmetrical mitosis to the normal asymmetrical pattern. Mitochondria in cancer cells drive the metabolic shifts and retrograde signalling to the genome, and their numbers and functionality correspond to the aggressiveness of the disease. Since the aberrant metabolism of cancer cell mitochondria can be corrected, it suggests a possible path to actually healing the cancer cell. Natural medicine candidates with pre-clinical and limited clinical evidence demonstrating the ability to correct cancer cell metabolism and mitochondria include quercetin (Batiha et al 2020, Zhang et al 2005, Das et al 2020, Jones et al 2017, Kothan et al 2004, Langner et al 2019, Ikegawa et al 2002, Suolinna et al 1975), R-alpha lipoic acid (da Veiga Moreira et al 2021, Humphries and Szweda1998, Korotchkina et al 2004, Moffa et al 2019, Wenzel et al 2005), thiamine (Parkhomenko et al 1987, Sheline et al 2002), acetyl-L-carnitine (Hoang et al 2007, Wenzel et al 2005), phloretin (Abdel-Wahab et al 2019, Choi 2019, Tang and Gong 2021), grapeseed proanthocyanidins (Nguyen and Pandey 2019), Coenzyme Q10 (Berbel-Garcia et al 2004, Smith et al 2008), Solomon’s seal (Polygonatum spp.) lectins, and blackseed (Nigella sativa) thymoquinone (Tavakkoli et al 2017). A ketogenic diet appears to be supportive of this positive metabolic shift, as does fasting.

Common clinical doses of candidate substances for metabolic regulation:

• Acetyl-L-carnitine 1000mg tid.
• Alpha lipoic acid 300mg bid R-ALA or 600mg bid if DL-ALA.
• May also be administered by IV 150mg twice a week, or by nebulization 50-100mg bid.
• Berberine 300-500mg bid Coenzyme Q10 – 300mg qd of ubiquinone or 100mg of ubiquinol.
• Curcumin -120mg bid of TheraCurmin™ or bid water-soluble curcumin extract.
• Fermented wheat germ extract (FWGE) 9g qd – bid.
• Grapeseed extract 250mg bid.
• Hydroxycitrate from Garcinia cambogia 1000mg bid.
• Phloretin 1000mg bid.
• Quercetin 1000mg bid, less if in liposomal format, delivering up to 140mg bid of dihydroquercetin.
• Red wine 1 glass daily.
• Resveratrol 250mg bid.
• Sodium bicarbonate – up to ½tsp bid.
• Solomon’s seal aerial herb Polygonatum spp. (minus seeds which are toxic) 5:1 tincture – 30 drops (½tsp) bid.
• Thymoquinone, from blackseed Nigella sativa, 100-200mg bid.
• Vitamin A retinol 25000IU retinol or 30000IU palmitate daily, but lower to 5,000IU if ALT or AST are over 300.
• Vitamin B1 – 100-200mg bid as thiamine, or 160mg bid as Benfotiamine™.

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