Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells

Andries M. Bergman, Herbert M. Pinedo, Godefridus J. Peters

Research output: Contribution to journalArticlepeer-review

Abstract

Gemcitabine is phosphorylated by deoxycytidine kinase and thymidine kinase 2 and during S-phase incorporated into DNA. The steroids cortisol and dexamethasone, which regulate cell proliferation and gene expression, are pumped out of the cell by the membrane efflux pumps P-glycoprotein and multidrug resistance-associated protein (MRP), which are blocked by verapamil. In parental non-small cell lung cancer (NSCLC) cells (SW1573), 5 μM cortisol and 100 nM dexamethasone decreased sensitivity to gemcitabine. However, both cortisol and dexamethasone only decreased sensitivity with verapamil in MRP (2R120) and P-glycoprotein (2R160) overexpressing variants. Cortisol decreased deoxycytidine kinase activity in SW1573 cells and cortisol with verapamil in 2R120 and 2R160 cells. Dexamethasone with verapamil decreased deoxycytidine kinase activity in 2R160. Cortisol decreased thymidine kinase 2 activity in 2R120 and 2R160 cells. Dexamethasone decreased thymidine kinase 2 activity in SW1573, 2R120 and 2R160 cells. In conclusion, since dexamethasone is frequently used to treat side effects of oncolytic therapy, a decrease of sensitivity to gemcitabine by steroids might be clinically relevant.

Original languageEnglish (US)
Pages (from-to)19-24
Number of pages6
JournalEuropean Journal of Pharmacology
Volume416
Issue number1-2
DOIs
StatePublished - Mar 23 2001
Externally publishedYes

Keywords

  • Corticosteroid
  • Deoxycytidine kinase activity
  • Gemcitabine
  • Multidrug resistance
  • NSCLC (non-small cell lung cancer)
  • Thymidine kinase 2 activity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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