Staurosporine increases toxicity of gemcitabine in non-small cell lung cancer cells: role of protein kinase C, deoxycytidine kinase and ribonucleotide reductase
| Autor: | J. Sigmond, Godefridus J. Peters, Willem J.P Loves, Eveline K. Hoebe, Andries M. Bergman, Leticia G. Leon |
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| Přispěvatelé: | Other departments, Medical oncology, Pathology, Medical oncology laboratory, CCA - Innovative therapy |
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Antimetabolites Antineoplastic Lung Neoplasms Deoxycytidine chemistry.chemical_compound Carcinoma Non-Small-Cell Lung Cell Line Tumor Deoxycytidine Kinase Ribonucleotide Reductases medicine Staurosporine Humans Pharmacology (medical) Enzyme Inhibitors Lung cancer Protein kinase C Protein Kinase C Pharmacology Chemistry Drug Synergism Deoxycytidine kinase medicine.disease Gemcitabine Ribonucleotide reductase Oncology Cancer research Phosphorylation medicine.drug |
| Zdroj: | Sigmond, J, Bergman, A M, Leon, L G, Loves, W J P, Hoebe, E K & Peters, G J 2010, ' Staurosporine increases toxicity of gemcitabine in non-small cell lung cancer cells: role of protein kinase C, deoxycytidine kinase and ribonucleotide reductase ', Anti-Cancer Drugs, vol. 21, no. 6, pp. 591-599 . https://doi.org/10.1097/CAD.0b013e32833a3543 Anti-cancer drugs, 21(6), 591-599. Lippincott Williams and Wilkins Anti-Cancer Drugs, 21(6), 591-599. Lippincott Williams and Wilkins |
| ISSN: | 1473-5741 0959-4973 |
| DOI: | 10.1097/CAD.0b013e32833a3543 |
| Popis: | 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. Anti-Cancer Drugs 21:591-599 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins |
| Databáze: | OpenAIRE |
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