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Rapid Induction of Apoptosis by Combination of Flavopiridol and Tumor Necrosis Factor (TNF)- or TNF-related Apoptosis-inducing Ligand in Human Cancer Cell Lines

LG Life Sciences, Ltd./R&D Park, Drug Discovery Institute, Daejeon, 305-380, Korea

Flavopiridol is one of the first cyclin-dependent kinase inhibitors undergoing clinical tests. We found that the combination treatment of flavopiridol (100–500 nM) with tumor necrosis factor (TNF)- (10 ng/ml) induced a rapid and eminent apoptosis, 20 ± 5% in 6-h treatment, in a human non-small cell lung carcinoma cell line, A549, as determined by the increase of sub-G₁ fraction in flow cytometry. A similar observation was also made in human colon cancer cell lines, HCT-116 and HCT-15, but not in Rat2, a rat fibroblast cell line. In A549 cells, the cytotoxic synergy by the combination treatment involved the activation of caspase-1, caspase-3, and caspase-8 and generated huge chromosomal degradation. The treatment schedules were so important that only the treatments of flavopiridol concomitantly with or followed by TNF- showed the pronounced apoptosis in A549 cells. Prior treatment of TNF- inhibited the apoptosis by the following combination treatment, leading to little cell death. Yet, such inhibition was reversed when 100 µM of 5,6-dichloro-1-ß-D-ribofuranosyl-benzimidazole, a transcription inhibitor, was present during the TNF- pretreatment, suggesting that the inhibitory pretreatment of TNF- might involve antiapoptotic gene expression at the transcriptional level. TNF- treatment resulted in nuclear factor (NF)-B activation, revealed by NF-B activity reporter assay. In contrast, flavopiridol was found to inhibit the NF-B-dependent gene transcription, which might give an explanation for the synergistic effect of flavopiridol with TNF-. TNF-related apoptosis-inducing ligand (TRAIL; 100 ng/ml) also caused a rapid and strong cytotoxic synergy with flavopiridol. In contrast to TNF-, however, all of the treatment sequences supported the synergy by TRAIL and flavopiridol. The combination of flavopiridol with TNF- or TRAIL may be of use for the development in cancer therapy.

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