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17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma

Jyh-Cheng Chen1, Peng-Fang Ma2, Yuan-Cheng Lin2

  • 1Department of Food Science, National Chiayi University, Chiayi, Taiwan.

Pharmacology
|June 29, 2018
PubMed

Insights

Heat shock protein 90 (Hsp90) inhibition enhances etoposide chemotherapy for non-small cell lung cancer (NSCLC) by reducing Xeroderma pigmentosum complementation group C (XPC) expression. This approach increases etoposide

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Etoposide (VP16) is a topoisomerase II inhibitor used in non-small cell lung cancer (NSCLC) treatment.
  • Xeroderma pigmentosum complementation group C (XPC) protein plays a role in DNA repair and NSCLC cell regulation.
  • Heat shock protein 90 (Hsp90) stabilizes oncogenic proteins, making it a therapeutic target.

Purpose of the Study:

  • To investigate if Hsp90 inhibition enhances etoposide-induced cytotoxicity in NSCLC cells by modulating XPC expression.
  • To explore the role of AKT signaling in etoposide's effect on XPC expression and cytotoxicity.

Main Methods:

  • Utilized etoposide and Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on NSCLC cell lines (H1703, H520).
  • Employed siRNA for XPC knockdown and PI3K inhibitor (LY294002) to inactivate AKT.
  • Used enforced expression of XPC cDNA and constitutively active AKT (AKT-CA) to assess their effects.

Main Results:

  • Etoposide increased XPC expression via AKT activation in NSCLC cells.
  • XPC knockdown or AKT inactivation potentiated etoposide's cytotoxic effects.
  • Enforced XPC or AKT expression reduced etoposide's cytotoxicity and growth inhibition.
  • 17-AAG enhanced etoposide's cytotoxicity by downregulating XPC and inactivating AKT.

Conclusions:

  • Hsp90 inhibition, through XPC downregulation, enhances etoposide-induced cytotoxicity in NSCLC cells.
  • The AKT signaling pathway is implicated in the regulation of XPC by etoposide.
  • Targeting Hsp90 in combination with etoposide may represent a viable therapeutic strategy for NSCLC.
Keywords:
AKTEtoposideHeat shock protein 90Lung squamous cell carcinomaXeroderma pigmentosum complementation group C

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