Mechanism explains why omega-3 fatty acids are toxic to tumor cells

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In their article Cell Metabolism, Belgian researchers highlight the ability of docosahexaenoic acid (DHA), under certain acidic conditions, to induce programmed cell death that can slow the progression of the disease.

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

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

“The well-established relationship between tumor acidosis and disease progression, including increased invasiveness, drug resistance and immune defense, makes supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-PUFA) a particularly relevant strategy that needs to be implemented.”

Programmed cell death

In a series of experiments, the UCLouvain team began to investigate whether excessive intake of certain FS could lead to anti-tumor effects.

They found that omega-3 as well as omega-6 PUFAs selectively induced programmed cell death, known as ferroptosis, in cancer cells under ambient acidosis conditions.

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

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

The team also looked at the dietary intake of long-chain omega-3 PUFAs, with tumor growth being significantly delayed in mice compared to a diet rich in monounsaturated FA.

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

Proof of PUFA effectiveness

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

The study further emphasizes that the effects were only observed in response to PUFAs, not monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs).

In addition, the anti-tumor effects in the omega-6 and omega-3 PUFA series were observed in direct proportion to the number of double bonds, which supports an intrinsic chemical effect rather than a change in signaling pathways driven by PUFA metabolites.

“The peroxidation by-products MDA and 4-HHE were significantly increased in tumors of mice that were fed a DHA-rich diet,” emphasized the team.

“The ferroptosis inhibitor ferrostatin reduced the tumor growth inhibiting effects of the DHS-rich diet, the ferroptosis inducer sulfasalazine further enhanced the cancer-inhibiting effects of this diet.”

Source: Cell Metabolism

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

“The peroxidation of polyunsaturated n-3 and n-6 ​​fatty acids in the acidic tumor environment leads to ferroptosis-mediated anti-cancer effects.”

Authors: Emeline Dierge et al

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