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New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent

Iwona Rzeszutek1, Martyna Cybularczyk-Cecotka2, Anna Deręgowska1

  • 1Institute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, Poland.

Journal of Medicinal Chemistry
|September 25, 2024
PubMed

Insights

Mito-fisetin, a novel compound, effectively targets mitochondria to induce apoptosis in senescent estrogen receptor-positive breast cancer cells. This mitochondrial targeting strategy shows promise for overcoming drug resistance in cancer therapy.

Area of Science:

  • Mitochondrial biology
  • Cancer therapeutics
  • Drug resistance

Background:

  • Mitochondria are key targets for cancer treatment.
  • Estrogen receptor (ER)-positive breast cancer presents challenges, especially in senescent states.
  • Drug resistance in senescent cancer cells necessitates novel therapeutic strategies.

Purpose of the Study:

  • To synthesize and evaluate the anticancer activity of mito-fisetin, a fisetin derivative conjugated with a triphenyl phosphonium cationic group.
  • To investigate the efficacy of mito-fisetin against both proliferating and senescent ER-positive breast cancer cells in vitro and in vivo.
  • To elucidate the molecular mechanisms underlying mito-fisetin's cytotoxicity, focusing on mitochondrial function and cellular stress responses.

Main Methods:

  • Synthesis of triphenyl phosphonium cationic group-conjugated fisetin (mito-fisetin).
  • In vitro and in vivo studies using cellular models of ER-positive breast cancer (proliferating and senescent states).
  • Analysis of mitochondrial membrane potential, oxidative stress, apoptosis induction, key protein levels (AMPK, AKT, HSP90), and mitophagic response markers.

Main Results:

  • Mito-fisetin effectively induced apoptosis in senescent breast cancer cells at low micromolar concentrations.
  • The compound dissipated mitochondrial membrane potential, increased oxidative stress, and impaired mitochondrial function.
  • Cytotoxicity was linked to increased phosphorylated AMPK, decreased AKT and HSP90, and inhibited mitophagy.
  • Senescent cells demonstrated higher sensitivity to mito-fisetin compared to proliferating cells.

Conclusions:

  • Mitochondrial targeting with mito-fisetin is a promising anticancer strategy.
  • This approach shows potential for eliminating drug-resistant senescent breast cancer cells.
  • Mito-fisetin represents a potential senotherapeutic agent for overcoming treatment resistance in ER-positive breast cancer.

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