[ARTICLE] Long chain unsaturated fat is cytotoxic for cancer cells

Killing tumour cells by fatty indigestion: here is the strategy to fight cancer, explored by Belgian scientists from Louvain University. Their work, recently published in Cell Metabolism(1), provided many convincing arguments from in vitro and animal experiments. Not all fats were found to be effective: polyunsaturated fatty acids (PUFAs) were, while saturated or monounsaturated ones were not. The more unsaturated the lipids, the more active they were. The cytotoxicity of PUFAs was amplified when tumour cells were grown in an acidic milieu, which is the normal condition of tumour environment. 

In vitro, PUFA overload into hungry tumour cells induces lipoperoxidation under acidic conditions, then triggers cell death by ferroptosis 

By dissecting the mechanisms of action of this nutritional strategy, the researchers observed that tumour cells (colorectal or hypopharyngeal lines in the experimental model), greedy for lipids, incorporated them above their storage capacity in the form of triglyceride droplets, free fatty acids and phospholipids. PUFAs, either from the omega 3 and omega 6 families, preferentially accumulated into acidic cancer cells. Then, these excess PUFAs underwent peroxidation after depletion of the cell’s antioxidant capacities. Indeed, the double bonds of these long chain lipids are very sensitive to oxidative stress. Concomitantly, the deficit in free radical scavenging systems triggered an iron-dependent programmed cell death process, called ferroptosis. This phenomenon was further boosted when adding molecules (diacylglycerol acyltransferase inhibitors, or DGATi) that prevent the incorporation of PUFAs into triglycerides. In doing so, they made PUFAs more prone to undergo peroxidation and induce ferroptosis. To sum up, the fatty acids were all the more toxic to cancer cells when the environment was acid, when fatty acids were polyunsaturated, and when they were not protected into buffered droplets.  

The same toxic mechanism is observed in mice fed fish-oil 

These promising results were not only obtained in vitro in 2D cell cultures, but were further confirmed in 3D spheroid models made of the same cancer cell lines, which spontaneously developed acidosis. The next experimental step consisted in transposing the model in vivo: mice were fed for two weeks with olive oil (rich in the monounsaturated oleic acid) or fish oil (rich in the omega 3 docosahexaenoic acid, or DHA), then injected with cancer cells. Interestingly, tumour growth was delayed and survival of animals was longer in mice fed fish oil, compared to those fed olive oil, and even more in mice treated with DGATi. All the observations tended to confirm that dietary PUFAs reached the tumour and exerted their cytotoxicity through induction of ferroptosis, after exhaustion of oxidative defences and lipoperoxydation, as seen in vitro. 

What if the strategy was applied to humans? The question remains to be addressed. But the idea of using nutrition to optimize therapeutic treatments against cancer is very exciting! To date, dietary supplementation with long chain PUFA has shown no clear benefit in cancer prevention, as concluded from a systematic review and meta-analysis of randomised control trials(2). But this should not prejudge its effectiveness as a treatment, especially in acidic, drug-resistant, and/or pro-invasive tumours. According to the authors, the greediness of cancer cells for PUFAs would make them vulnerable, and the combination of this fatty nutritional approach with DGATi appears relevant and very promising. Following this perspective, a Chinese team recently published positive results on a ferroptosis-inducing lipid nano-particle targeted against resistant prostate cancer in mice(3).  

References:

1. Dierge E, Debock E, Guilbaud C, Corbet C, Mignolet E, Mignard L, 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 Aug 3;33(8):1701-1715.e5. doi: 10.1016/j.cmet.2021.05.016. Epub 2021 Jun 11. PMID: 34118189. 

2. Hanson, S., Thorpe, G., Winstanley, L. et al. Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials. Br J Cancer 122, 1260–1270 (2020). https://doi.org/10.1038/s41416-020-0761-6 

3. Chen J, Wang Y, Han L, Wang R, Gong C, Yang G, Li Z, Gao S, Yuan Y. A ferroptosis-inducing biomimetic nanocomposite for the treatment of drug-resistant prostate cancer. Mater Today Bio. 2022 Nov 3;17:100484. doi: 10.1016/j.mtbio.2022.100484. PMID: 36388460; PMCID: PMC9649379.