Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death

Abstract

Background/Aims: Rapamycin (Rp), the main mammalian target of rapamycin complex inhibitor, is a promising therapeutic agent for breast cancer. However, metabolic disorders and drug resistance reduce its efficacy. Epidemiological, clinical, and experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) significantly reduce the incidence and mortality of breast cancer and improve metabolic disorders. Methods: Three breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Rp plus ω-3 PUFA treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics, seahorse experiments, and western blot analysis. Results: We found that ω-3 PUFAs and Rp synergistically induced cell cycle arrest and apoptosis in vitro and in vivo, accompanied by autophagy blockage. In addition, Rp-induced hypertriglyceridemia and hypercholesterolemia were completely abolished by ω-3 PUFA supplementation. Moreover, the combined treatment of ω-3 PUFA and Rp significantly inhibited glycolysis and glutamine metabolism. The anti-tumor effects of this combination treatment were dependent on ROS production, which was increased by β-oxidation and oxidative phosphorylation. Conclusion: Our study revealed that ω-3 PUFA enhanced the anti-tumor activity of Rp while minimizing its side effects in vitro and in vivo. These results provide novel insights into the mechanisms underlying the potential beneficial effects of Rp combined with ω-3 PUFAs on the prevention of breast cancer.

Targeting ferroptosis in breast cancer

“…In 2018, Zhu et al reported a synergistic effect of n-3 PUFAs and rapamycin (Rp) in breast cancer cell cycle arrest, apoptosis and autophagy blockage in vitro and in vivo. They noticed that combined treatment of n-3 PUFAs and Rp significantly inhibited glycolysis and glutamine metabolism, and the antitumour effects of this combination treatment were dependent on β-oxidation and oxidative phosphorylation-mediated ROS production [242].…”

The roles of glucose metabolic reprogramming in chemo- and radio-resistance

“…A new study has found that autophagy is a major way of down-regulating cell metabolism, leading to cancer cell quiescence, survival, and chemo-resistance [85, 86]. The up-regulation of autophagy mediated by metabolic dysfunction could contribute to a common mechanism of resistance to chemotherapy and radiotherapy by suppressing apoptosis, such as rapamycin (Rp) [87–89]. In addition, the induction of autophagy may defend against epirubicin-mediated apoptosis, act as a pro-survival factor, and thus lead to deficient apoptosis in HepG2 and A549 cells [90–92].…”

Selective Anticancer Properties, Proapoptotic and Antibacterial Potential of Three Asplenium Species

“…Previous phytochemical studies on A. ceterach , A. trichomanes and A. scolopendrium used for preparation of the extracts for the present investigation have shown that A. ceterach contains the highest levels of tannins and ω-3 polyunsaturated fatty acids (PUFAs) [ 13 ]. Both types of compounds are known for their various positive bioactivities, including anticancer effects [ 22 , 24 , 25 ]. This fact also supports the highest inhibitory effects detected for A. ceterach .…”

“…This fact also supports the highest inhibitory effects detected for A. ceterach . Recently, it has been reported that ω-3 PUFA could potentiate the anticancer activity of therapeutic agents by induction of reactive oxygen species (ROS) followed by apoptosis [ 25 ]. These findings support our data, which suggest increased ROS levels following treatment with A. cetera extracts based on the detected elevated SOD activity.…”