Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor, which has recently entered clinical trials. However, when administered as a single agent against solid tumors, the antitumor actions of flavopiridol have been primarily cytostatic. Given its reported effects on cell cycle regulation, transcription, and apoptosis, flavopiridol may also influence cellular radioresponse. Thus, to evaluate the potential for combining this cyclin-dependent kinase inhibitor with radiation as a cancer treatment strategy, we have investigated the effects of flavopiridol on the radiation sensitivity of two human prostate cancer cell lines (DU145 and PC3). The data presented here indicate that exposure to flavopiridol (60-90 nM) after irradiation enhanced the radiosensitivity of both DU145 and PC3 cells. This sensitization occurred in the absence of significant reductions in cell proliferation, retinoblastoma protein phosphorylation, or P-TEFb activity. Moreover, the post-irradiation addition of flavopiridol had no effect on radiation-induced apoptosis or the activation of the G2 cell cycle checkpoint. However, flavopiridol did modify the time course of gammaH2AX expression in irradiated cells. Whereas there was no significant difference in radiation-induced gammaH2AX foci at 6 h, at 24 h after irradiation, the number of cells expressing gammaH2AX foci was significantly greater in the flavopiridol-treated cells. These results indicate that flavopiridol can enhance radiosensitivity of human tumor cells and suggest that this effect may involve an inhibition of DNA repair.
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PMID:Flavopiridol enhances human tumor cell radiosensitivity and prolongs expression of gammaH2AX foci. 1507 84

Human cytomegalovirus (HCMV) infection leads to dysregulation of multiple cell cycle-regulatory proteins. In this study, we examined the effects of inhibition of cyclin-dependent kinase (cdk) activity on viral replication. With the drug Roscovitine, a specific inhibitor of cyclin-dependent kinases 1, 2, 5, 7, and 9, we have shown that during the first 6 h of infection, cyclin-dependent kinase-dependent events occurred that included the regulated processing and accumulation of the immediate-early (IE) UL122-123 transcripts and UL36-37 transcripts. Altered processing of UL122-123 led to a loss of IE1-72 and an increase in IE2-86. The ratio of spliced to unspliced UL37 transcripts also changed. These effects did not require de novo protein synthesis or degradation of proteins by the proteasome. Addition of Roscovitine at the beginning of the infection was also associated with inhibition of expression of selected viral early gene products, viral DNA replication, and late viral gene expression. When Roscovitine was added after the first 6 h of infection, the effects on IE gene expression were no longer observed and viral replication proceeded through the late phase, but viral titers were reduced. The reduction in viral titer was observed even when Roscovitine was first added at 48 h postinfection, indicating that cyclin-dependent kinase activity is required at both IE and late times. Flavopiridol, another specific inhibitor of cyclin-dependent kinases, had similar effects on IE and early gene expression. These results underscore the importance of accurate RNA processing and reiterate the significant role of cell cycle-regulatory factors in HCMV infection.
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PMID:Cyclin-dependent kinase activity is required at early times for accurate processing and accumulation of the human cytomegalovirus UL122-123 and UL37 immediate-early transcripts and at later times for virus production. 1545 41

Several lines of evidence show that cyclin-dependent kinases (CDKs) contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis. Given their role in the neuronal apoptosis, the inhibition of CDKs by specific drugs such as flavopiridol may be a valid therapeutic approach. Expression of CDKs was observed in rodent models of excitotoxicity and stroke, and CDK inhibitors showed neuroprotective effects. Flavopiridol may provide significant improvement in neurodegenerative diseases in humans.
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PMID:Flavopiridol: an antitumor drug with potential application in the treatment of neurodegenerative diseases. 1553 27

Flavopiridol and UCN-01 are two novel protein kinase inhibitors with diverse cellular effects that may complement each other with regards to induction of apoptosis. HeLa cells engineered to overexpress human survivin (HeLa-S) were at least approximately 4.8-fold resistant to UCN-01 relative to proliferation observed in control HeLa cells (HeLa-V). Flavopiridol cytotoxicity as measured using the MTT assay was unaffected in HeLa-S cells when compared with HeLa-V cells. Similarly, simultaneous treatment of HeLa-V cells with flavopiridol and UCN-01 for 72 hours did not result in synergistic inhibition of proliferation; however, in HeLa-S cells, this combination resulted in synergistic inhibition of cell proliferation. Flavopiridol and UCN-01 augmented apoptosis in HeLa-S cells (as compared with HeLa-V cells) as measured by caspase-3 cellular activity assay, DNA fragmentation and PARP cleavage by western blot. In HeLa-V and -S cells, combination treatment resulted in caspase-8 cleavage. Caspase-9 was expressed in HeLa-V cells; however, there was a marked reduction of caspase-9 content in HeLa-S cells only. Combination treatment resulted in a significant reduction in survivin abundance in HeLa-S and SKBR3-UR cells, but not in their respective parental lines. The synergy of Flavopiridol and UCN-01 are selectively toxic to survivin-overexpressing cell lines and the mechanism of toxicity involves caspase-dependent cell death.
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PMID:A study of cytotoxic synergy of UCN-01 and flavopiridol in syngeneic pair of cell lines. 1601 89

The complex mechanism of cell division in trypanosomatids is not completely fully understood. CRKs (cdc2-related kinases), Cyclins and CKSs (cdc2-kinase subunit) are involved in the progression through the cell cycle. The CKS proteins were first described as components of the cell cycle machinery in yeast and their action has been implicated in the regulation of CDK function. In the present work we identified Tcp12CKS1 a member of the CKS family in the parasite Trypanosoma cruzi. TcCKS1 is expressed in the three forms of T. cruzi. By using anti-Tcp12CKS1 antiserum, protein kinase (PK) activities were immunoprecipitated. The PK activity level varies depending on the stage analyzed, being lower in trypomastigotes and thus suggesting that different stages have different CKS-CRK complexes. Moreover, these PK activities were inhibited by using Flavopiridol, a known CDKs inhibitor. Western blot analyses demonstrated that in the epimastigote stage, p12CKS1 stably interacts with TcCRK1 and TcCRK3. In addition, Tcp12CKS1 was able to rescue the p13SUC1 null mutant of S. pombe. The functional complementation between the CKS proteins of two evolutionary distant organisms supports the role of Tcp12CKS1 as a key regulator in T. cruzi cell cycle.
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PMID:Trypanosoma cruzi Tcp12CKS1 interacts with parasite CRKs and rescues the p13SUC1 fission yeast mutant. 1653 Aug 62

Flavopiridol was one of the first cyclin-dependent kinase inhibitors demonstrated to have an antitumor effect in several cancer types. Here, we investigated the effects of flavopiridol on TNF-related apoptosis-inducing ligand (TRAIL) in the human hepatocellular carcinoma (HCC) cell lines HLE and HepG2, and evaluated the role of flavopiridol in apoptosis. To better understand the mechanism of increased TRAIL sensitivity in HCC cells, we determined the effect of flavopiridol on cell surface expression of TRAIL and TRAIL receptors using flow cytometry analysis. The levels of survivin, FLIP, Bcl-xL and X-chromosome-linked IAP (XIAP) in treated and untreated cells was also determined. Flavopiridol decreased cell viability in a dose-dependent manner in the two HCC cell lines tested. The pan-caspase inhibitor z-VAD-FMK did not inhibit the effect. However, subtoxic levels of flavopiridol dramatically enhanced TRAIL-induced apoptosis in both cells. Flavopiridol up-regulated TRAIL, TRAIL-R1 and TRAIL-R2 in both cell lines. In addition, flavopiridol down-regulated expression of survivin in both cell lines, and expression of FLIP and Bcl-xL were down-regulated in HLE cells. In summary, flavopiridol augmented TRAIL sensitivity by up-regulation of TRAIL receptors and down-regulation of survivin, FLIP and Bcl-xL. Thus, combining flavopiridol with a TRAIL agonist may prove to be an effective new strategy for treatment of HCC.
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PMID:The cyclin-dependent kinase inhibitor flavopiridol sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis. 1682 Sep 31

Purpose. Flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor that has preclinical activity in many tumours. This synthetic flavonoid was tested in a phase II nonrandomized, nonblinded multicentre clinical trial to determine its activity and toxicity in patients with previously untreated metastatic or locally advanced soft tissue sarcoma. Methods. A total of 18 patients with histologically confirmed nonoperable soft tissue was treated with flavopiridol administered at a dose of 50 mg/m(2) IV over 1 hour daily x3 days every 3 weeks. Results. Eighteen patients were accrued to the study over a period of 6 months. No objective responses were noted in the seventeen evaluable patients. Eight patients (47%) exhibited stable disease after 2 cycles (median duration of 4.3 months (range 1.4-6.9 months). Kaplan-Meier estimates for 3- and 6-month progression-free survivial rates were 44 percent and 22 percent, respectively. The only grade 3 toxicities were diarrhea (N = 2), nausea (N = 2), gastritis (N = 1), and fatigue (N = 1). Ninety-four percent of patients received >/= 90% of the planned dose intensity, during 55 treatment cycles. Conclusions. Flavopiridol was well tolerated at the dose and schedule used in this study, however, no objective treatment responses were seen and thus our results do not support further exploration of flavopiridol as a monotherapy at this dose and schedule in soft tissue sarcomas.
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PMID:A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma. 1725 59

Multimodal therapies play important roles in the treatment of osteosarcoma (OS) and Ewing's family of tumors (EFTs), two most frequent malignant bone tumors. Although the clinical outcome of primary OS and EFTs is greatly improved, the relapsed cases often are associated with multidrug resistance of the tumors and the prognosis of these patients is still poor. Flavopiridol, a pan cyclin-dependent kinase (CDK) inhibitor is a novel antitumor agent that can induce cell cycle arrest and apoptosis in many cancer cells. However, there have been no studies about the effects of flavopiridol on drug-resistant OS and EFTs. Here, we demonstrated that flavopiridol induced the cleavage of poly-ADP-ribose polymerase (PARP) in a time and dose dependent manner in adriamycin-resistant OS and EFTs cells expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP(1)) as effectively as in their parental cells. Our data also showed that flavopiridol caused the release of mitochondrial cytochrome c and the activation of caspase-9, caspase-8 and caspase-3, with an increase ratio of the proapoptotic protein level (Bax) to the antiapoptotic protein level (Bcl-2 and Bcl-X(L)), while apoptosis was inhibited by pan caspase inhibitor (Z-VAD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK), not by caspase-8 inhibitor (Z-IETD-FMK). The treatment with flavopiridol further inhibited the tumor growth in mouse models of the drug-resistant OS and EFTs. These results suggest that flavopiridol might be promising in clinical therapy for the relapsed OS and EFTs.
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PMID:Cyclin-dependent kinase inhibitor, flavopiridol, induces apoptosis and inhibits tumor growth in drug-resistant osteosarcoma and Ewing's family tumor cells. 1752 Jun 76

The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in clinical trials. Future approaches to determine clinical benefit need to incorporate both the lessons learned from these early compounds and information recently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key concepts that should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.
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PMID:CDK inhibitors in cancer therapy: what is next? 1805

Traumatic brain injury (TBI) causes both direct and delayed tissue damage. The latter is associated with secondary biochemical changes such as cell cycle activation, which leads to neuronal death, inflammation, and glial scarring. Flavopiridol--a cyclin-dependent kinase (CDK) inhibitor that is neither specific nor selective--is neuroprotective. To examine the role of more specific CDK inhibitors as potential neuroprotective agents, we studied the effects of roscovitine in TBI. Central administration of roscovitine 30 mins after injury resulted in significantly decreased lesion volume, as well as improved motor and cognitive recovery. Roscovitine attenuated neuronal death and inhibited activation of cell cycle pathways in neurons after TBI, as indicated by attenuated cyclin G1 accumulation and phosphorylation of retinoblastoma protein. Treatment also decreased microglial activation after TBI, as reflected by reductions in ED1, galectin-3, p22(PHOX), and Iba-1 levels, and attenuated astrogliosis, as shown by decreased accumulation of glial fibrillary acidic protein. In primary cortical microglia and neuronal cultures, roscovitine and other selective CDK inhibitors attenuated neuronal cell death, as well as decreasing microglial activation and microglial-dependent neurotoxicity. These data support a multifactorial neuroprotective effect of cell cycle inhibition after TBI--likely related to inhibition of neuronal apoptosis, microglial-induced inflammation, and gliosis--and suggest that multiple CDKs are potentially involved in this process.
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PMID:Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. 1861 15


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