Identification of GL-V9 as a novel senolytic agent against senescent breast cancer cells

Life Sci. 2021 May 1:272:119196. doi: 10.1016/j.lfs.2021.119196. Epub 2021 Feb 19.

Abstract

Senescent cancer cells contribute to tumor refractoriness. The removal of senescent cells after chemotherapy prevents or delays cancer relapse. Our study showed that GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a potential anticancer drug, eliminated senescent MEFs (Mouse embryonic fibroblasts) and drug-induced senescent breast cancer cells. GL-V9 induced apoptosis in senescent MDA-MB-231 cells. Mechanistically, it alkalized lysosomes and increased the abundance of mitochondria as well as ROS (Reactive oxygen species). The senolytic effect of GL-V9 was also observed in epirubicin-treated mammary tumors in MMTV-PyMT mice. Our data thus indicated that GL-V9 is a promising senolytic drug which could be used to improve the outcome of cancer chemotherapy.

Keywords: Autophagy; Breast cancer; GL-V9; ROS; Senolytics.

MeSH terms

  • Aging / physiology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cellular Senescence / drug effects*
  • Cellular Senescence / physiology
  • China
  • Female
  • Flavonoids / metabolism
  • Flavonoids / pharmacology*
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / prevention & control
  • Reactive Oxygen Species / pharmacology
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl)butoxy)4H-chromen-4-one
  • Antineoplastic Agents
  • Flavonoids
  • Reactive Oxygen Species