A novel synthesized cyclohexane-hydroxytyrosol derivative suppresses ovarian cancer cell growth through inducing ROS and blocking autophagic flux

Aims: Drug resistance in ovarian cancer (OC) cells often leads to recurrence, metastasis, and high mortality rates among OC patients. Hydroxytyrosol (HT) has been reported to inhibit the proliferation of ovarian and other types of cancer cells. Here we synthesized a novel cyclohexane-hydroxytyrosol derivative (Chx-HT) for enhanced anticaner efficacy. We examined the growth-suppressing effect of Chx-HT on OC cells in vitro and in xenograft mouse model and investigated the underlying mechanism. Results: We demonstrated that Chx-HT inhibits proliferation, promotes apoptosis, remodels glucose and lipid metabolism by reducing fatty acid β-oxidation while increasing glycolysis, de novo fatty acid synthesis and lipid droplet accumulation, impairs mitochondrial respiration and induces oxidative stress both in vitro and in vivo. Additionally, Chx-HT blocks autophagic flux by obstructing the maturation of lysosomal cathepsins in the late-stage, but also activates autophagy through the p-AMPK/p-mTOR/p-ULK1 pathway in response to energy deficit. Innovation and Conclusion: ROS plays a critical role in mediating the effects of Chx-HT on proliferation, apoptosis, autophagy, TCA cycle, FAO and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo fatty acid synthesis, and lipid droplet accumulation in ovarian cancer cells. Cotreating OC cells with Chx-HT and autophagic inhibitor or glycolytic inhibitor results in an additive inhibition of proliferation. Our study indicates that Chx-HT stands for a promising OC therapeutic by ROS and autophagy blockade mediated metabolic remodeling.