1. Academic Validation
  2. A Novel Synthesized Cyclohexane-Hydroxytyrosol Derivative Suppresses Ovarian Cancer Cell Growth Through Inducing Reactive Oxidative Species and Blocking Autophagic Flux

A Novel Synthesized Cyclohexane-Hydroxytyrosol Derivative Suppresses Ovarian Cancer Cell Growth Through Inducing Reactive Oxidative Species and Blocking Autophagic Flux

  • Antioxid Redox Signal. 2024 Mar 27. doi: 10.1089/ars.2023.0400.
Guanfei Zhang 1 Min Wang 1 Yilin Gao 1 Aikaterini Christina Komianou 2 Eleftheria A Georgiou 2 Yan Wang 1 Yezi Zheng 1 Jiankang Liu 1 3 Ioannis K Kostakis 2 Lin Zhao 1
Affiliations

Affiliations

  • 1 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Cardiometabolic Innovation Center, Ministry of Education, Department of Cardiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
  • 2 Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece.
  • 3 School of Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
Abstract

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 a xenograft mouse model and investigated the underlying mechanism. Results: We demonstrated that Chx-HT inhibits proliferation, promotes Apoptosis, and remodels glucose and lipid metabolism by reducing fatty acid β-oxidation while increasing glycolysis, de novo fatty acid synthesis (FAS), and lipid droplet (LD) accumulation, impairs mitochondrial respiration, and induces oxidative stress both in vitro and in vivo. In addition, 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: Reactive oxidative species (ROS) play a critical role in mediating the effects of Chx-HT on proliferation, Apoptosis, Autophagy, tricarboxylic acid (TCA) cycle, fatty acid β-oxidation, and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo FAS, and LD accumulation in OC 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.

Keywords

autophagy; cyclohexane-hydroxytyrosol; glucose and lipid metabolism; ovarian cancer; reactive oxidative species.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163456
    Anti-tumor Agent