Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells.
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 microM 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.
Bergman
A M
AM
Department of Oncology, VU Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, Netherlands.
Pinedo
H M
HM
Peters
G J
GJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D000093542:Gemcitabine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003841:Deoxycytidine; D003907:Dexamethasone; D014700:Verapamil; D003842:Deoxycytidine Kinase; D006854:Hydrocortisone; D000093542:Gemcitabine