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4β-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells

Jen-Yang Tang1,2,3, Hurng-Wern Huang4, Hui-Ru Wang4

  • 1Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Environmental Toxicology
|November 23, 2017
PubMed

Insights

4β-hydroxywithanolide (4βHWE) selectively kills oral cancer cells by inducing reactive oxygen species (ROS) and DNA damage. This mechanism involves oxidative DNA damage and DNA double strand breaks (DSB), offering a targeted therapeutic approach.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Reactive oxygen species (ROS) induction is implicated in 4β-hydroxywithanolide (4βHWE) mediated cancer cell death.
  • The precise mechanisms of ROS involvement and DNA damage in 4βHWE's selective killing of oral cancer cells remain incompletely understood.

Purpose of the Study:

  • To investigate the role of ROS and oxidative DNA damage in 4βHWE-induced selective oral cancer cell death.
  • To elucidate the molecular pathways involving DNA double strand breaks (DSB) and oxidative damage.

Main Methods:

  • Cell viability, morphology, ROS generation, and DNA damage markers (γH2AX foci, DSB signaling proteins, 8-oxo-2'deoxyguanosine [8-oxodG]) were assessed in oral cancer (Ca9-22) and normal (HGF-1) cells treated with 4βHWE.
  • Free radical scavenger N-acetylcysteine (NAC) was used to confirm ROS involvement.
  • Immunofluorescence, western blotting, comet assay, and flow cytometry were employed to detect DNA damage.

Main Results:

  • 4βHWE reduced oral cancer cell viability and induced ROS generation, effects reversed by NAC.
  • Increased γH2AX foci and overexpression of DSB signaling proteins (γH2AX, MRN complex) were observed in 4βHWE-treated oral cancer cells.
  • Elevated levels of oxidative DNA damage marker 8-oxodG were detected in oral cancer cells, with both DSB and oxidative damage being reversible by NAC pretreatment.

Conclusions:

  • 4βHWE selectively induces DNA double strand breaks and oxidative DNA damage in oral cancer cells.
  • These effects are mediated by ROS and contribute to the selective killing of oral cancer cells.
  • 4βHWE demonstrates potential as a targeted therapeutic agent for oral cancer.
Keywords:
4β-hydroxywithanolide EDNA double strand breakoxidative DNA damagereactive oxygen speciesselective killing

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