When Bill Lane’s book ‘Sharks Don’t Get Cancer’ was published in 1992, it made quite a splash. It spawned a shoal of shark cartilage extracts which sold at inflated prices to cancer sufferers, without much effect. One of these, Bill’s own product Benefin, was trialed in patients with advanced cancer and found wanting (1). The hurdle may have been set too high and the product might conceivably have done better in earlier cases, but we will never know.
Another extract, Neovastat, was demonstrated to have angiostatic properties and showed promise in various pre-clinical models of cancer (2). Four subsequent clinical trials failed, again, to provide convincing proof of concept.
Lane’s sequel, the peevishly titled ‘Sharks Still Don’t Get Cancer’ came out in 1996, but the truth is that sharks do get cancer (3). Just not very often, as far as we know (4). This is because their genome is twice the size of ours, and codes for some very sophisticated repair systems (5). They are better at repairing damaged DNA than we are (5), which is cancer-protective; and better at healing in general (6). As genome decay is strongly linked to ageing you would expect sharks to have long life spans and Great Whites do, reputedly achieving 70 years and more (7).
Sadly, and despite Hollywood’s best efforts (8), we cannot yet hybridize shark and human DNA – though the companies currently pushing mRNA therapies (9-11) would, if they thought there was a fin in it. There are plenty more fish in the sea, however, and while sharks have fallen out of favor the omega 3 fatty acid DHA found in oily fish, cold-water marine algae and Balance oil, is emerging as a more substantial cancer-killer.
Epidemiological studies show a reasonably consistent link between fatty fish consumption and reduced colorectal, prostate and breast cancers (ie 12-14), and a growing body of evidence shows how this might be working.
DHA is avidly taken up by cell membranes (15) where it induces membrane re-modelling (16) and multiple protective cellular responses. These include enhanced anti-inflammatory activity and oxidative stress responses, and the protective activation of peroxisome proliferator-activated receptors (17, 18). In normal cells these actions are entirely positive; in cancer cells however DHA and its metabolites inhibit growth and metastasis (19, 20), and trigger the form of cell death called apoptosis (ie 20, 21). But that’s not all they do.
Cancer cells have dis-regulated cell membranes (22) and if they are force-fed DHA it accumulates in their membranes and interior, driving up lipid peroxidation (23). If this reaches a threshold level it kills the cancer cell via a different death sequence, called ferroptosis (24-26). Ferroptosis may be more clinically important than apoptosis and is dependent on polyunsaturated fatty acids and the trace element iron. Selenium and vitamin E are also involved, on the other (cyto-protective) side of the equation.
Selenium indirectly (via the enzyme system glutathione peroxidase 4), and vitamin E directly reduce lipid peroxidation, and therefore ferroptosis (26). This is not a reason to avoid these two micronutrients as they have chemoprotective properties (ie 27, 28). Inhibiting ferroptosis is also a valid strategy in reducing the risk of neurodegenerative (29) and hepatic (30) diseases, which develop in membrane-dense environments.
If you love vitamin E but hate cancer, members of the vitamin E family other than the commercially used d-alpha tocopherol appear to be more chemo-protective (31). A full spectrum tocopherol / tocotrienol mix is probably, therefore, a better way to go.
Back to PUFA’s and iron.
The fact that the modern diet is depleted in omega 3 HUFA’s and iron probably makes some contribution to our dizzying cancer rates. Conversely, it raises the prospect of targeted nutritional intervention.
This is being developed by researchers at the Belgian University of Louvain, who followed a trail that began in 1920 when Otto Warburg discovered that cancer cells rely on fermentation.
As tumors tend to be poorly vascularized, cancer cells within the tumor are hypoxic. This forces them to make a series of metabolic alterations. These include switching from phosphorylative oxidation to fermentation, which makes the cells’ microenvironment more acidic, and switching from glucose to fatty acids as their main energy source (32, 33).
The acidosis boosts production of TGF-beta, which is a Janus molecule. In the early stages of cancer low levels of TGF-beta are protective as they slow cell growth and promote apoptosis (34). Successful cancers however develop the ability to turn TGF-beta to their own purposes, and use it as a supercharger (34).
In more developed cancers, high levels of TGF-beta make cancer cells more aggressive and more invasive (35, 36). TGF-beta is also a key regulator of immune tolerance, and by increasing lipid droplet formation in local dendritic (immune) cells, it turns down the local immune response (35, 36). This one-two punch is great from the cancer’s p.o.v. and essential for the next step on its road to clinical significance, but is obviously very bad news for the host.
Fortunately for us cancer cells’ generally increased rates of growth and metabolism, which makes them so dangerous, is also their Achilles’ heel. They are already under oxidative stress and adding polyunsaturated fatty acids, which contain multiple double bonds and are prone to oxidation, imposes further oxidative stress. Here is a potentially selective anti-cancer mechanism.
The Louvain team found that by feeding cancer cells on PUFA’s, the increased peroxidative stress in their membranes reliably caused cancer cell death by ferroptosis (37). The scientists’ preferred agent was the omega 3 fatty acid DHA which, with six double bonds to EPA’s five, is more prone to peroxidation and therefore better at triggering ferroptosis.
Arachidonic acid, an omega 6 PUFA with four double bonds was only slightly less effective in culture, but is not recommended for clinical use. In a human, high doses of AA would increase inflammation, encouraging metastatic spread and working against any tumoricidal activity.
Cancer cells do have a partial defense against ferroptosis, again involving TGF-beta. As the tumor environment becomes more acidic, rising TGF-beta levels increase lipid storage in droplets in the cancer cell’s cytoplasm (36). The cells do this to shield PUFA’s from peroxidation, but that storage capacity is limited. DHA loading overwhelms the limits and then overspill, peroxidation and ferroptosis ensue (37).
The Louvain group showed that DHA’s ability to kill cancer cells is enhanced if co-administered with diacylglycerol acyltransferase inhibitors which prevent droplet formation, reducing intracellular lipid storage and thus facilitating DHA overflow (37). They used drugs to achieve this, but their work opens the door to a more advanced nutritional intervention.
When the energy-sensor AMP-kinase is activated, it leads to the breakdown of lipid droplet proteins called perilipins, and to the reduction of lipid droplet capacity (38). AMP-kinase is activated by physical exercise (39) and exercise therefore reduces PUFA storage, increasing the ferroptotic death of cancer cells. This is one reason why exercise reduces the risk of cancer (40); along with mTOR down-regulation (41, 42). AMP-kinase is also activated by certain polyphenols (43) and by dammaranes (44), saponins derived from the medicinal herb Gynostemma pentaphylum.
The polyphenols are especially interesting because they appear to inhibit diacylglycerol acyltransferases via multiple mechanisms (45-47). Based on the above science, combining high dose DHA with polyphenols and AMP-kinase activation using exercise or a validated Gynostemma extract such as ActivAMP (44, 48), should increase the ferroptotic killing of cancer cells.
I am not the first to come up with this strategy. More than a half century ago, the Romanian Ana Aslan was apparently treating her cancer patients in a broadly similar way.
In the mid 70’s I talked with an older colleague at the Institute of Psychiatry in London who had visited Dr Aslan in her clinic in Timissoara twenty years previously. If I remember correctly, her cancer patients were put on what we now understand to be an anti-inflammatory regime. This included a diet of fresh fruits, vegetables and fish, no sugar, no smoking, dental extractions if there was any gingival disease, and strenuous exercise. Tobacco was banned.
There appeared to be no method in her madness and yet the treatment, based presumably on her empirical knowledge, was reputedly effective in slowing cancer; and logical in retrospect.
There is a place for analysis and investigation, and a complementary place for empirical knowledge. We need both.
Next week: When to eat, and when not to eat.
- Loprinzi CL, Levitt R, Barton DL, Sloan JA, Atherton PJ, Smith DJ, Dakhil SR, Moore DF Jr, Krook JE, Rowland KM Jr, Mazurczak MA, Berg AR, Kim GP; North Central Cancer Treatment Group. Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. 2005 Jul 1;104(1):176-82.
- Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
- Finkelstein JB. Sharks do get cancer: few surprises in cartilage research. J Natl Cancer Inst. 2005 Nov 2;97(21):1562-3.
- Ostrander GK, Cheng KC, Wolf JC, Wolfe MJ. Shark cartilage, cancer and the growing threat of pseudoscience. Cancer Res. 2004;64:8485–8491.
- Marra NJ, Stanhope MJ, Jue NK, Wang M, Sun Q, Pavinski Bitar P, Richards VP, Komissarov A, Rayko M, Kliver S, Stanhope BJ, Winkler C, O’Brien SJ, Antunes A, Jorgensen S, Shivji MS. White shark genome reveals ancient elasmobranch adaptations associated with wound healing and the maintenance of genome stability. Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4446-4455.
- Chin A, Mourier J, Rummer JL. Blacktip reef sharks (Carcharhinus melanopterus) show high capacity for wound healing and recovery following injury.Conserv Physiol. 2015;3:cov062.
- Hamady LL,Natanson LJ, Skomal GB, Thorrold SR. Vertebral Bomb Radiocarbon Suggests Extreme Longevity in White Sharks. PLoS ONE, 2014; 9 (1): e84006
- Nuovo GJ, Magro C, Shaffer T, Awad H, Suster D, Mikhail S, He B, Michaille JJ, Liechty B, Tili E. Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein. Ann Diagn Pathol. 2021 Apr;51:151682.
- Goldman M, Hermans C. Thrombotic thrombocytopenia associated with COVID-19 infection or vaccination: Possible paths to platelet factor 4 autoimmunity. PLoS Med. 2021 May 24;18(5):e1003648.
- Kim J, Lim SY, Shin A, Sung MK, Ro J, Kang HS, Lee KS, Kim SW, Lee ES. Fatty fish and fish omega-3 fatty acid intakes decrease the breast cancer risk: a case-control study. BMC Cancer. 2009 Jun 30;9:216.
- Berquin I., Edwards I., Chen Y. Multi-targeted therapy of cancer by omega-3 fatty acids.Cancer Lett. 2008;269:363–377.
- Zheng JS, Hu XJ, Zhao YM, Yang J, Li D. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. 2013 Jun 27;346:f3706.
- Calder P.C. Docasahexaenoic acid. Nutr. Metab. 2016;69:8–21.
- Fuentes NR, Kim E, Fan YY, Chapkin RS. Omega-3 fatty acids, membrane remodeling and cancer prevention. Mol Aspects Med. 2018 Dec;64:79-91.
- Liu J, Ma DW. The role of n-3 polyunsaturated fatty acids in the prevention and treatment of breast cancer. 2014;6:5184–5223.
- Stillwell W.S., Shaikh S.R., Zerouga M., Siddiqui R., Wassall S.R. Docosahexaenoic acid affects cell signalling by altering lipid rafts. Nutr. Dev. 2005;45:559–579.
- West L, Yin Y, Pierce SR, Fang Z, Fan Y, Sun W, Tucker K, Staley A, Zhou C, Bae-Jump V. Docosahexaenoic acid (DHA), an omega-3 fatty acid, inhibits tumor growth and metastatic potential of ovarian cancer. Am J Cancer Res. 2020 Dec 1;10(12):4450-4463.
- Bai X, Shao J, Zhou S, Zhao Z, Li F, Xiang R, Zhao AZ, Pan J. Inhibition of lung cancer growth and metastasis by DHA and its metabolite, RvD1, through miR-138-5p/FOXC1 pathway.J Exp Clin Cancer Res. 2019;38:479.
- D’Eliseo D, Velotti F. Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy. J Clin Med. 2016 Jan 26;5(2):15.
- Galeotti T, Borrello S, Minotti G, Masotti L. Membrane alterations in cancer cells: the role of oxy radicals. Ann N Y Acad Sci. 1986;488:468-80.
- Gonzalez M.J., Schemmel R.A., Dugan L.J., Gray J.I., Welsch C.W. Dietary fish oil inhibits human breast carcinoma growth: A function of increased lipid peroxidation. 1993;28:827–832.
- Du J, Wang T, Li Y, Zhou Y, Wang X, Yu X, Ren X, An Y, Wu Y, Sun W, Fan W, Zhu Q, Wang Y, Tong X. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin.Free Radic Biol Med. 2019;131:356–369.
- Ou W, Mulik RS, Anwar A, McDonald JG, He X, Corbin IR. Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma. Free Radic Biol Med. 2017 Nov;112:597-607.
- Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis. 2020 Feb 3;11(2):88.
- Cai X, Wang C, Yu W, Fan W, Wang S, Shen N, Wu P, Li X, Wang F. Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-regression. Sci Rep. 2016 Jan 20;6:19213.
- Hall KT, Buring JE, Mukamal KJ, Vinayaga Moorthy M, Wayne PM, Kaptchuk TJ, Battinelli EM, Ridker PM, Sesso HD, Weinstein SJ, Albanes D, Cook NR, Chasman DI. COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials. J Natl Cancer Inst. 2019 Jul 1;111(7):684-694.
- Ren JX, Sun X, Yan XL, Guo ZN, Yang Y. Ferroptosis in Neurological Diseases. Front Cell Neurosci. 2020 Jul 13;14:218.
- Mao L, Zhao T, Song Y, Lin L, Fan X, Cui B, Feng H, Wang X, Yu Q, Zhang J, Jiang K, Wang B, Sun C. The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope? Cell Death Dis. 2020 Jul 9;11(7):518.
- Jiang Q. Natural Forms of Vitamin E as Effective Agents for Cancer Prevention and Therapy. (2017). Advances in Nutrition 8(6), 850–867
- Belisario DC, Kopecka J, Pasino M, Akman M, De Smaele E, Donadelli M, Riganti C. Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance. 2020 Dec 4;9(12):2598.
- Corbet C, Pinto A, Martherus R, Santiago de Jesus JP, Polet F, Feron O. Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation. Cell Metab. 2016 Aug 9;24(2):311-23.
- Syed V. TGF-β Signaling in Cancer. J Cell Biochem. 2016 Jun;117(6):1279-87. doi: 10.1002/jcb.25496.
- Trempolec N, Degavre C, Doix B, Brusa D, Corbet C, Feron O. Acidosis-Induced TGF-β2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response. Cancers (Basel). 2020 May 19;12(5):1284.
- Corbet C, Bastien E, Santiago de Jesus JP, Dierge E, Martherus R, Vander Linden C, Doix B, Degavre C, Guilbaud C, Petit L, Michiels C, Dessy C, Larondelle Y, Feron O. TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nat Commun. 2020 Jan 23;11(1):454
- Dierge E, Debock E, Guilbaud C, Corbet C, Mignolet E, Mignard E, Bastien E, Dessy C,Larondelle Y, Feron O. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 2021 Jun 8:S1550-4131(21)00233-3.
- Kaushik S, Cuervo AM. AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. 2016;12(2):432-8.
- Jessen N, Sundelin EI, Møller AB. AMP kinase in exercise adaptation of skeletal muscle. Drug Discov Today. 2014 Jul;19(7):999-1002
- Patel AV, Friedenreich CM, Moore SC, Hayes SC, Silver JK, Campbell KL, Winters-Stone K, Gerber LH, George SM, Fulton JE, Denlinger C, Morris GS, Hue T, Schmitz KH, Matthews CE. American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Med Sci Sports Exerc. 2019 Nov;51(11):2391-2402.
- Agostini D, Natalucci V, Baldelli G, De Santi M, Donati Zeppa S, Vallorani L, Annibalini G, Lucertini F, Federici A, Izzo R, Stocchi V, Barbieri E. New Insights into the Role of Exercise in Inhibiting mTOR Signaling in Triple-Negative Breast Cancer. Oxid Med Cell Longev. 2018 Sep 30;2018:5896786.
- Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci. 2020 Mar 10;10:31.
- Singh D.K., Banerjee S., Porter T.D. Green and black tea extracts inhibit hmg-coa reductase and activate amp kinase to decrease cholesterol synthesis in hepatoma cells. Nutr. Biochem. 2009;20:816–822.
- Ha TKQ, Pham HTT, Cho HM, Tran VO, Yang JL, Jung DW, Williams DR, Oh WK. 12,23-Dione dammarane triterpenes from Gynostemma longipes and their muscle cell proliferation activities via activation of the AMPK pathway. Sci Rep. 2019 Feb 4;9(1):1186.
- Rom O, Volkova N, Jeries H, Grajeda-Iglesias C, Aviram M. Rom O, Volkova N, Jeries H, Grajeda-Iglesias C, Aviram M. Exogenous (Pomegranate Juice) or Endogenous (Paraoxonase1) Antioxidants Decrease Triacylglycerol Accumulation in Mouse Cardiovascular Disease-Related Tissues. 2018 Nov;53(11-12):1031-1041.
- Velliquette RA, Grann K, Missler SR, Patterson J, Hu C, Gellenbeck KW, Scholten JD, Randolph RK.Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial. Nutr Metab (Lond). 2015 Aug 6;12:27.
- Kowalska K, Dembczyński R, Gołąbek A, Olkowicz M, Olejnik A. ROS Modulating Effects of Lingonberry (Vaccinium vitis-idaea) Polyphenols on Obese Adipocyte Hypertrophy and Vascular Endothelial Dysfunction. Nutrients. 2021 Mar 9;13(3):885.