Staurosporine increases toxicity of gemcitabine in non-small cell lung cancer cells: role of protein kinase C, deoxycytidine kinase and ribonucleotide reductase.
Gemcitabine, a deoxycytidine analog, active against non-small cell lung cancer, is phosphorylated by deoxycytidine kinase (dCK) to active nucleotides. Earlier, we found increased sensitivity to gemcitabine in P-glycoprotein (SW-2R160) and multidrug resistance-associated protein (SW-2R120), overexpressing variants of the human SW1573 non-small cell lung cancer cells. This was related to increased dCK activity. As protein kinase C (PKC) is higher in 2R120 and 2R160 cells and may control the dCK activity, we investigated whether gemcitabine sensitivity was affected by the protein kinase C inhibitor, staurosporine, which also modulates the cell cycle. Ten nmol/l staurosporine enhanced the sensitivity of SW1573, 2R120 and 2R160 cells 10-fold, 50-fold and 270-fold, respectively. Staurosporine increased dCK activity about two-fold and the activity of thymidine kinase 2, which may also activate gemcitabine. Staurosporine also directly increased dCK in cell free extracts. Staurosporine decreased expression of the free transcription factor E2F and of ribonucleotide reductase (RNR), a target for gemcitabine inhibition. In conclusion, staurosporine may potentiate gemcitabine by increasing dCK and decreasing E2F and RNR, which will lead to a more pronounced RNR inhibition.
Sigmond
Jennifer
J
Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Bergman
Andries M
AM
Leon
Leticia G
LG
Loves
Willem J P
WJ
Hoebe
Eveline K
EK
Peters
Godefridus J
GJ
D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D003842:Deoxycytidine Kinase; D011493:Protein Kinase C; D019311:Staurosporine; D000093542:Gemcitabine