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.
Article
en En
| MEDLINE
| ID: mdl-38407966
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 ß-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 andConclusion:
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 ß-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_ovary_cancer
Idioma:
En
Revista:
Antioxid Redox Signal
Asunto de la revista:
METABOLISMO
Año:
2024
Tipo del documento:
Article