Abstract

Membrane lipid therapy is a novel approach to rationally design or discover therapeutic molecules that target membrane lipids. This strategy has been used to design synthetic fatty acid analogues that are currently under study in clinical trials for the treatment of cancer. In this context, and with the aim of controlling tumor cell growth, we have designed and synthesized a hydroxylated analogue of triolein, hydroxytriolein (HTO). Both triolein and HTO regulate the biophysical properties of model membranes and they inhibit the growth of non-small lung cancer cell lines in vitro. The molecular mechanism underlying the anti-proliferative effect of HTO involves regulation of the lipid membrane structure, PKCα and ERK activation, the production of reactive oxygen species (ROS) and autophagy. In vivo studies on a mouse model of non-small cell lung cancer showed that HTO but not triolein impairs tumor growth, which could be associated with the relative resistance of HTO to enzymatic degradation. The data presented explain in part why olive oil (whose main component is the triacylglyceride triolein) is preventive but not therapeutic, and they demonstrate a potent effect of HTO against cancer. HTO shows a good safety profile, it can be administered orally, and it does not induce non-tumor cell (fibroblast) death in vitro or side effects in mice, reflecting its specificity for cancer cells. For these reasons, HTO is a good candidate as a drug to combat cancer that acts by regulating lipid structure and function in the cancer cell membrane.