Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavopiridol, the first potent cyclin-dependent kinase inhibitor to undergo clinical trials as an antineoplastic agent in the United States, has attracted considerable attention because of its unique cellular targets and its ability to kill noncycling tumor cells in vitro. To better understand how flavopiridol might be used clinically, the present study used colony-forming assays to examine the cytotoxicity resulting from combining flavopiridol with eight other antineoplastic agents in four different administration schedules in A549 human non-small cell lung carcinoma cells in vitro. Cytotoxic synergy, as assessed by the median effect method, resulted when flavopiridol was combined with seven of the eight tested antineoplastic agents but was highly dependent upon administration schedule. Cisplatin was the only agent that resulted in sequence-independent synergy when combined with flavopiridol. For paclitaxel, cytarabine, topotecan, doxorubicin, and etoposide, synergy was more pronounced when the agents were administered before flavopiridol rather than concomitant with or following flavopiridol. Examination suggested that this sequence dependence reflected arrest of cells in G1 and G2 phases of the cell cycle during and for 24 h following flavopiridol treatment. Interestingly, 48-72 h after flavopiridol removal, the fraction of surviving cells in S phase increased 2-3-fold relative to untreated controls. Consistent with these results, administration of flavopiridol for 24 h followed 3 days later by exposure to an S phase-active agent (cytarabine or 5-fluorouracil) resulted in a highly synergistic interaction. These results highlight the importance of administration schedule when combining flavopiridol with other agents and provide a starting point for examining the effect of flavopiridol in drug combinations in vivo.
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PMID:Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. 926 99

The anti-tumor drug Flavopiridol is a potent inhibitor of cyclin-dependent kinases (cdks). As a consequence, Flavopiridol-treated cells arrest in both G1 and G2, but Flavopiridol has also been shown to be cytotoxic for some tumor cell lines. The underlying molecular events are, however, unclear. We now show that Flavopiridol induces apoptosis in human umbilical vein endothelial cells (HUVECs), as judged by the occurrence of classical apoptotic markers, including chromatin condensation, internucleosomal cleavage, DNA fragmentation (TUNEL assay), annexin V binding and poly(ADP-ribose) polymerase (PARP)-cleavage. Such induction of apoptosis occurs with equal efficiency in both proliferating and G0/G1-arrested cells. Because growth-arrested HUVECs lack cdk2 activity and contain high levels of the cdk inhibitor p27, our observations suggest that cell cycle regulated cdks may not be the only critical target for Flavopiridol-induced apoptosis. Surprisingly, A549 lung carcinoma cells were clearly dependent on cell proliferation for the induction of cell death, pointing to cell type-related differences in the mechanism of Flavopiridol action.
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PMID:Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. 963 6

Flavopiridol (L86-8275) ((-)-cis-5, 7-dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hydroxy-1-methyl)-piperidinyl] -4H-benzopyran-4-one), a potential antitumor drug, currently in phase II trials, has been shown to be an inhibitor of muscle glycogen phosphorylase (GP) and to cause glycogen accumulation in A549 non-small cell lung carcinoma cells (Kaiser, A., Nishi, K., Gorin, F.A., Walsh, D.A., Bradbury, E. M., and Schnier, J. B., unpublished data). Kinetic experiments reported here show that flavopiridol inhibits GPb with an IC(50) = 15.5 microm. The inhibition is synergistic with glucose resulting in a reduction of IC(50) for flavopiridol to 2.3 microm and mimics the inhibition of caffeine. In order to elucidate the structural basis of inhibition, we determined the structures of GPb complexed with flavopiridol, GPb complexed with caffeine, and GPa complexed with both glucose and flavopiridol at 1.76-, 2.30-, and 2.23-A resolution, and refined to crystallographic R values of 0.216 (R(free) = 0.247), 0.189 (R(free) = 0.219), and 0.195 (R(free) = 0.252), respectively. The structures provide a rational for flavopiridol potency and synergism with glucose inhibitory action. Flavopiridol binds at the allosteric inhibitor site, situated at the entrance to the catalytic site, the site where caffeine binds. Flavopiridol intercalates between the two aromatic rings of Phe(285) and Tyr(613). Both flavopiridol and glucose promote the less active T-state through localization of the closed position of the 280s loop which blocks access to the catalytic site, thereby explaining their synergistic inhibition. The mode of interactions of flavopiridol with GP is different from that of des-chloro-flavopiridol with CDK2, illustrating how different functional parts of the inhibitor can be used to provide specific and potent binding to two different enzymes.
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PMID:Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. 1092 12

Flavopiridol treatment can lead to apoptosis via a mechanism that has been associated with down-regulation of Mcl-1. Likewise, recent studies from our laboratory demonstrated that E2F1 leads to transcriptional repression of Mcl-1 and subsequently apoptosis. Given the ability of cyclin/cyclin-dependent kinase 2 antagonists to kill transformed cells, we surmised that flavopiridol may stabilize E2F1 and enhance apoptosis via repression of Mcl-1. Here we demonstrate that flavopiridol is associated with a dose-dependent increase in E2F1 protein levels, a corresponding reduction in Mcl-1, and apoptosis in H1299 lung carcinoma cells. Treatment of H1299 cells with 200 nM flavopiridol resulted in the rapid elevation of E2F1 and reduction in Mcl-1 levels within 12 h of treatment. The elevation of E2F1 and reduction in Mcl-1 clearly preceded the induction of apoptosis. Both H1299 and NIH3T3 fibroblast cell lines that constitutively express Mcl-1 under the control of the cytomegalovirus promoter have no reductions in Mcl-1 levels with flavopiridol treatment and are resistant to apoptosis induced by flavopiridol. H1299 cells that have E2F1 deleted through RNAi vector targeting are less sensitive to flavopiridol-induced cell death, and likewise, mouse embryo fibroblast cell lines deficient in E2F1 are less susceptible to apoptosis induced by flavopiridol compared with wild-type control fibroblasts. These data suggest that apoptosis induced by flavopiridol is dependent on the enhancement of E2F1 levels and the repression of Mcl-1.
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PMID:Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. 1253 75

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)-alpha (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-G(1) 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-alpha showed the pronounced apoptosis in A549 cells. Prior treatment of TNF-alpha inhibited the apoptosis by the following combination treatment, leading to little cell death. Yet, such inhibition was reversed when 100 microM of 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, a transcription inhibitor, was present during the TNF-alpha pretreatment, suggesting that the inhibitory pretreatment of TNF-alpha might involve antiapoptotic gene expression at the transcriptional level. TNF-alpha treatment resulted in nuclear factor (NF)-kappa B activation, revealed by NF-kappa B activity reporter assay. In contrast, flavopiridol was found to inhibit the NF-kappa B-dependent gene transcription, which might give an explanation for the synergistic effect of flavopiridol with TNF-alpha. TNF-related apoptosis-inducing ligand (TRAIL; 100 ng/ml) also caused a rapid and strong cytotoxic synergy with flavopiridol. In contrast to TNF-alpha, however, all of the treatment sequences supported the synergy by TRAIL and flavopiridol. The combination of flavopiridol with TNF-alpha or TRAIL may be of use for the development in cancer therapy.
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PMID:Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. 1256 5