Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines.
Farnesyltransferase inhibitor (FTI) induces apoptosis of transformed cells. This involves changes in mitochondria, including decrease of mitochondrial membrane potential and the release of cytochrome c. The released cytochrome c then induces events leading to the activation of caspase-3. In this study, we report that purine derivative cyclin-dependent kinase (Cdk) inhibitors, roscovitine and olomoucine, dramatically enhance this FTI-induced apoptosis of human cancer cell lines. We noticed the synergy between Cdk inhibitors and FTI through our screen to identify compounds that enhance FTI-induced apoptosis of promyelocytic leukemic cell line HL-60. The Cdk inhibitors by themselves do not induce apoptosis at the concentrations used. Roscovitine synergizes with FTI to release cytochrome c from mitochondria. In addition, we detected synergistic effects of FTI and roscovitine to inhibit hyperphosphorylation of retinoblastoma protein. Enhancement of FTI-induced apoptosis by roscovitine is not unique to HL-60 cells, since similar synergy was observed with a leukemic cell line CEM and a prostate cancer cell line LNCaP. In LNCaP cells, in addition to roscovitine and olomoucine, phophatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, was effective in enhancing FTI-induced apoptosis. However, the effects of roscovitine appear to be distinct from those of LY294002, since roscovitine did not affect Akt activity while LY294002 significantly decreased the activity of Akt. Our finding of the synergy between FTI and Cdk inhibitor is significant for understanding the mechanism of action of FTI as well as for clinical use of FTI.
Edamatsu
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Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, CA 90095-1489, USA.
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Nemoto
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Guo
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Tamanoi
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D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007701:Kinetin; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D000077546:Roscovitine
D001552:Benzazepines; D002867:Chromones; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D009025:Morpholines; D011687:Purines; D016160:Retinoblastoma Protein; C121676:SCH 56582; D000077546:Roscovitine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C090046:olomoucine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018844:Cyclin-Dependent Kinases; D020169:Caspases; D007701:Kinetin