Is Pisces compatible with Cancer?

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.

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