Mechanism could explain why Omega-3 fatty acid is toxic to tumour cells

Writing in Cell Metabolism​, Belgian researchers highlight Docosahexaenoic Acid’s (DHA) ability to induce a programmed cell death under certain acidic conditions that may slow down disease progression.

“For an adult,”​ the Université catholique de Louvain (UCLouvain) researchers stated, “it’s recommended to consume at least 250 milligrams (mg) of DHA per day. ​

“But studies show that our diet provides on average only 50 to 100 mg per day. This is well below the minimum recommended intake.”​

“The well-established link between tumour acidosis and disease progression, including though increased invasiveness, drug resistance and immune escape, makes dietary omega-3 Long-Chain Polyunsaturated Fatty Acid (LC-PUFA) supplementation a particularly relevant strategy to be implemented.”​

Programmed cell death ​

In a series of experiments, the UCLouvain team began examining whether excess uptake of specific FAs could lead to antitumor effects.

They found that omega-3 but also omega-6 PUFA selectively induced the programmed cell death process known as ferroptosis in cancer cells under ambient acidosis conditions.

Upon noting that omega-3 but also omega-6 PUFA preferentially accumulate as lipid droplets in acidic cancer cells, the team also noted that excess LC-PUFAs undergo peroxidation (oxidative degradation of lipids) and induce ferroptosis.

This observation was intensified in the presence of diacylglycerol acyltransferase inhibitors (DGATi), a group of enzymes known to aid fat metabolism and transport.

The team also explored the inclusion of omega-3 long-chain PUFA in the diet with tumour growth significantly delayed amongst mouse subjects when compared with a monounsaturated FA-rich diet.

This effect was amplified by the inclusion of DGATi or ferroptosis inducers.

Evidence for PUFA efficacy​

“Mechanistically, we provide evidence that ferroptosis, an iron-dependent, non-apoptotic form of cell death associated with oxidised lipids is promoted when acidic cancer cells fail to buffer the enhanced uptake of PUFAs and expose themselves to the detrimental effects of peroxidation.”​

The study goes on to highlight the effects were only seen in response to PUFAs, but not Monounsaturated Fatty Acids (MUFAs) or Saturated Fatty Acids (SFAs).

Additionally, the antitumour effects were observed with the omega-6 and omega-3 PUFA series in direct proportion to the number of double bonds, supporting an intrinsic chemical effect instead of an alteration in signalling pathways driven by PUFA metabolites.

“Peroxidation by-products MDA and 4-HHE were significantly increased in tumours of mice fed a DHA-rich diet,” ​the team also pointed out.

“The ferroptosis inhibitor ferrostatin reduced the tumour growth inhibitory effects of the DHS-rich diet, the ferroptosis inducer sulfasalazine further enhanced the anticancer effects of that diet.”  ​

Source: Cell Metabolism​

Published online: doi.org/10.1016/j.cmet.2021.05.016​​

“Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects.”​

Authors: Emeline Dierge et al