The positive effects of rapamycin are strengthened and its side effects minimised by association with omega-3 PUFA
Breast cancer is the second leading cause of cancer death among women. Hormone therapy significantly increases survival in women with this type of cancer, but it is not effective in patients with triple-negative breast cancer (breast cancer cells negative for oestrogen receptors, progesterone receptors and HER2) or in those that develop endocrine resistance; thus combined strategies are often used with the aim of reducing toxicity and overcoming resistance to the drugs.
Signalling of the mammalian target of rapamycin (mTOR) is altered in various types of tumour, including breast cancer, and has been associated with its pathogenesis, progression and resistance to treatment. Rapamycin is the main inhibitor of the mTOR complex and a promising therapeutic agent in breast cancer, in which it has been shown to have anti-proliferative and pro-apoptotic effects. However, metabolic disorders and drug resistance reduce its efficacy. Furthermore, it seems more prone to lead to stabilisation than regression in most cancers.
Epidemiological, clinical and experimental studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) significantly reduce the incidence and mortality of breast cancer and also improve metabolic disorders.
A recent study performed in China with an experimental mouse model (immunocompetent and immunodeficient mice) and three breast cancer cell lines assessed the therapeutic effects of the association of rapamycin with omega-3 PUFA. The production of reactive oxygen species (ROS) and glucose uptake were measured by flow cytometry; metabolic changes were examined by metabolomics, the measurement of energy produced by cellular metabolism (Seahorse®), and a Western blot test was carried out.
The results showed that:
- The omega-3 PUFA and rapamycin synergistically induced cell cycle detention and apoptosis in vivo and in vitro, accompanied by autophagy blockade.
- Supplementation with omega-3 PUFA completely prevented rapamycin-induced hypertriglyceridemia and hypercholesterolemia.
- Combined therapy with omega-3 PUFA and rapamycin significantly inhibited glycolysis and glutamine metabolism.
- The anti-tumour effect of the combined therapy was dependent on ROS production, which increased with beta-oxidation and oxidative phosphorylation.
In summary, omega-3 PUFA improved the anti-tumour activity of rapamycin and minimised its side effects in vivo and in vitro.