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Danazol mediates collateral sensitivity via STAT3/Myc related pathway in multidrug-resistant cancer cells

Ying-Tzu Chang1, Yu-Ning Teng2, Kun-I Lin3,4

  • 1Department of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.

Scientific Reports
|August 14, 2019
PubMed

Insights

Danazol demonstrates collateral sensitivity (CS) against multidrug-resistant (MDR) cancer cells by inhibiting the STAT3 pathway. This synthetic steroid hormone offers a potential new strategy for overcoming cancer treatment resistance.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Multidrug resistance (MDR) significantly hinders effective cancer chemotherapy.
  • Collateral sensitivity (CS) offers a promising strategy by exploiting selective toxicity against MDR cancer cells.
  • Identifying novel CS drugs is crucial for overcoming therapeutic resistance.

Purpose of the Study:

  • To investigate the CS properties and cytotoxic mechanisms of danazol, a synthetic steroid hormone.
  • To evaluate danazol's efficacy against MDR cancer cells compared to natural hormones.
  • To elucidate the molecular pathways targeted by danazol in MDR cancer.

Main Methods:

  • In vitro cytotoxicity assays comparing danazol with natural hormones against MDR cancer cells.
  • Cell cycle analysis to determine cell cycle arrest.
  • Apoptosis assays (caspase-8 related).
  • Western blotting to assess STAT3 phosphorylation and expression of downstream genes (c-Myc, CDC25, CDK1, p21).
  • Molecular docking studies to predict danazol-STAT3 binding.

Main Results:

  • Danazol exhibited superior selective cytotoxicity against MDR cancer cells compared to natural hormones.
  • Danazol induced G2/M phase arrest and caspase-8-related apoptosis in MDR cancer cells.
  • Danazol significantly reduced STAT3 phosphorylation and the expression of STAT3-regulated survival genes (c-Myc, CDC25, CDK1).
  • Danazol upregulated the cell cycle inhibitor p21 in MDR cancer cells.
  • Docking studies indicated favorable binding of danazol to STAT3.

Conclusions:

  • Danazol exerts a collateral sensitivity effect in MDR cancer cells.
  • Danazol's mechanism involves the inhibition of the STAT3 signaling pathway.
  • Danazol represents a potential therapeutic agent for overcoming multidrug resistance in cancer.

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