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Chemical Compound Review

Alvocidib     2-(2-chlorophenyl)-5,7- dihydroxy-8-[(3R...

Synonyms: FLAVO, Flavoperidol, Flavopiridol, AC1NRALK, CHEMBL8817, ...
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Disease relevance of Flavopiridol


Psychiatry related information on Flavopiridol


High impact information on Flavopiridol

  • Accumulation of p27Luc in response to Cdk2 inhibitory drugs (flavopiridol and R-roscovitine) was demonstrable in human tumor cells in vivo using noninvasive bioluminescent imaging [7].
  • Surprisingly, the density of transcribing Pol II and Pol II progression through hsp70 in vivo are nearly normal in flavopiridol-treated cells [8].
  • Here, we show that flavopiridol, a highly specific P-TEFb kinase inhibitor, dramatically reduces the global levels of Ser2--but not Ser5--phosphorylated CTD at actively transcribed loci on Drosophila polytene chromosomes under both normal and heat shocked conditions [8].
  • Brief treatment of Drosophila cells with flavopiridol leads to a reduction in the accumulation of induced hsp70 and hsp26 RNAs [8].
  • Flavopiridol treatment also resulted in a remarkable reduction of cyclin D1 expression in HNSCC cells and tumor xenografts [1].

Chemical compound and disease context of Flavopiridol


Biological context of Flavopiridol


Anatomical context of Flavopiridol


Associations of Flavopiridol with other chemical compounds

  • Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis [9].
  • In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562 [18].
  • ABCG2 is a plasma membrane efflux pump that is able to confer resistance to several anticancer agents, including mitoxantrone, camptothecins, anthracyclines, and flavopiridol [19].
  • As with NGF deprivation and camptothecin treatment, the cyclin-dependent kinase inhibitors flavopiridol and olomoucine protected neurons from apoptosis induced by AraC and UV treatment [20].
  • Exposure of U937 monocytic leukemia cells to minimally toxic concentrations of flavopiridol (FP), roscovitine, or CGP74514A for 3 h in conjunction with the PI3K inhibitor LY294002 (abbreviated LY in the article) resulted in a marked decrease in Akt phosphorylation [21].
  • Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone [22].
  • Flavopiridol-induced mitochondrial depolarization was not blocked by caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2 overexpression [23].
  • Flavopiridol then doxorubicin sequential treatment was synergistic in the pRB-negative H69 cell line [24].
  • Preclinically, flavopiridol potentiated doxorubicin [25].
  • Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent [26].
  • The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib [27].

Gene context of Flavopiridol

  • Along with this inhibition, flavopiridol decreased total cyclin-D protein levels in this cell line [28].
  • In this study, we used MCF-7 breast carcinoma cells that are wild type for p53 and pRb positive and contain CDK4-cyclin D1 and MDA-MB-468 breast carcinoma cells that are mutant p53, pRb negative, and lack CDK4-cyclin D1 to investigate the G1 arrest produced by Flavopiridol [29].
  • Flavopiridol inhibited the in vitro kinase activity of CDK2 using an immune complex kinase assay (IC50, 100 nM at 400 microM ATP) [29].
  • Surprisingly, CDK4 immunoprecipitates derived from Flavopiridol-treated MCF-7 cells (3 h, 300 nM Flavonolpiridol) had an approximately 3-fold increased kinase activity compared with untreated cells [29].
  • Flavopiridol showed a minimal effect on the constitutive levels of VEGF mRNA but completely blocked hypoxia-induced VEGF mRNA and protein expression [30].

Analytical, diagnostic and therapeutic context of Flavopiridol


  1. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. Patel, V., Senderowicz, A.M., Pinto, D., Igishi, T., Raffeld, M., Quintanilla-Martinez, L., Ensley, J.F., Sausville, E.A., Gutkind, J.S. J. Clin. Invest. (1998) [Pubmed]
  2. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. De Azevedo, W.F., Mueller-Dieckmann, H.J., Schulze-Gahmen, U., Worland, P.J., Sausville, E., Kim, S.H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  3. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Byrd, J.C., Lin, T.S., Dalton, J.T., Wu, D., Phelps, M.A., Fischer, B., Moran, M., Blum, K.A., Rovin, B., Brooker-McEldowney, M., Broering, S., Schaaf, L.J., Johnson, A.J., Lucas, D.M., Heerema, N.A., Lozanski, G., Young, D.C., Suarez, J.R., Colevas, A.D., Grever, M.R. Blood (2007) [Pubmed]
  4. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts. Arguello, F., Alexander, M., Sterry, J.A., Tudor, G., Smith, E.M., Kalavar, N.T., Greene, J.F., Koss, W., Morgan, C.D., Stinson, S.F., Siford, T.J., Alvord, W.G., Klabansky, R.L., Sausville, E.A. Blood (1998) [Pubmed]
  5. Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors. Rathkopf, D., Dickson, M.A., Feldman, D.R., Carvajal, R.D., Shah, M.A., Wu, N., Lefkowitz, R., Gonen, M., Cane, L.M., Dials, H.J., Winkelmann, J.L., Bosl, G.J., Schwartz, G.K. Clin. Cancer Res. (2009) [Pubmed]
  6. Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Jorda, E.G., Verdaguer, E., Canudas, A.M., Jiménez, A., Bruna, A., Caelles, C., Bravo, R., Escubedo, E., Pubill, D., Camarasa, J., Pallàs, M., Camins, A. Neuropharmacology (2003) [Pubmed]
  7. Bioluminescent imaging of Cdk2 inhibition in vivo. Zhang, G.J., Safran, M., Wei, W., Sorensen, E., Lassota, P., Zhelev, N., Neuberg, D.S., Shapiro, G., Kaelin, W.G. Nat. Med. (2004) [Pubmed]
  8. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Ni, Z., Schwartz, B.E., Werner, J., Suarez, J.R., Lis, J.T. Mol. Cell (2004) [Pubmed]
  9. Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Dai, Y., Rahmani, M., Pei, X.Y., Dent, P., Grant, S. Blood (2004) [Pubmed]
  10. Suppression of HIV-1 expression by inhibitors of cyclin-dependent kinases promotes differentiation of infected podocytes. Nelson, P.J., Gelman, I.H., Klotman, P.E. J. Am. Soc. Nephrol. (2001) [Pubmed]
  11. Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Nguyen, D.M., Schrump, W.D., Chen, G.A., Tsai, W., Nguyen, P., Trepel, J.B., Schrump, D.S. Clin. Cancer Res. (2004) [Pubmed]
  12. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Byrd, J.C., Peterson, B.L., Gabrilove, J., Odenike, O.M., Grever, M.R., Rai, K., Larson, R.A. Clin. Cancer Res. (2005) [Pubmed]
  13. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Parker, B.W., Kaur, G., Nieves-Neira, W., Taimi, M., Kohlhagen, G., Shimizu, T., Losiewicz, M.D., Pommier, Y., Sausville, E.A., Senderowicz, A.M. Blood (1998) [Pubmed]
  14. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Chen, R., Keating, M.J., Gandhi, V., Plunkett, W. Blood (2005) [Pubmed]
  15. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Di Giovanni, S., Movsesyan, V., Ahmed, F., Cernak, I., Schinelli, S., Stoica, B., Faden, A.I. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  16. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Byrd, J.C., Shinn, C., Waselenko, J.K., Fuchs, E.J., Lehman, T.A., Nguyen, P.L., Flinn, I.W., Diehl, L.F., Sausville, E., Grever, M.R. Blood (1998) [Pubmed]
  17. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Kitada, S., Zapata, J.M., Andreeff, M., Reed, J.C. Blood (2000) [Pubmed]
  18. A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia. Chen, R., Gandhi, V., Plunkett, W. Cancer Res. (2006) [Pubmed]
  19. Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Chen, Z.S., Robey, R.W., Belinsky, M.G., Shchaveleva, I., Ren, X.Q., Sugimoto, Y., Ross, D.D., Bates, S.E., Kruh, G.D. Cancer Res. (2003) [Pubmed]
  20. Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress. Park, D.S., Morris, E.J., Stefanis, L., Troy, C.M., Shelanski, M.L., Geller, H.M., Greene, L.A. J. Neurosci. (1998) [Pubmed]
  21. The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Yu, C., Rahmani, M., Dai, Y., Conrad, D., Krystal, G., Dent, P., Grant, S. Cancer Res. (2003) [Pubmed]
  22. Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: a phase II trial in adults with poor-risk acute myelogenous leukemia. Karp, J.E., Smith, B.D., Levis, M.J., Gore, S.D., Greer, J., Hattenburg, C., Briel, J., Jones, R.J., Wright, J.J., Colevas, A.D. Clin. Cancer Res. (2007) [Pubmed]
  23. Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium. Hussain, S.R., Lucas, D.M., Johnson, A.J., Lin, T.S., Bakaletz, A.P., Dang, V.X., Viatchenko-Karpinski, S., Ruppert, A.S., Byrd, J.C., Kuppusamy, P., Crouser, E.D., Grever, M.R. Blood (2008) [Pubmed]
  24. Retinoblastoma tumor suppressor gene expression determines the response to sequential flavopiridol and doxorubicin treatment in small-cell lung carcinoma. Budak-Alpdogan, T., Chen, B., Warrier, A., Medina, D.J., Moore, D., Bertino, J.R. Clin. Cancer Res. (2009) [Pubmed]
  25. The cyclin-dependent kinase inhibitor flavopiridol potentiates Doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Luke, J.J., D'Adamo, D.R., Dickson, M.A., Keohan, M.L., Carvajal, R.D., Maki, R.G., de Stanchina, E., Musi, E., Singer, S., Schwartz, G.K. Clin. Cancer Res. (2012) [Pubmed]
  26. A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Holkova, B., Supko, J.G., Ames, M.M., Reid, J.M., Shapiro, G.I., Perkins, E.B., Ramakrishnan, V., Tombes, M.B., Honeycutt, C., McGovern, R.M., Kmieciak, M., Shrader, E., Wellons, M.D., Sankala, H., Doyle, A., Wright, J., Roberts, J.D., Grant, S. Clin. Cancer Res. (2013) [Pubmed]
  27. Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms. Holkova, B., Kmieciak, M., Perkins, E.B., Bose, P., Baz, R.C., Roodman, G.D., Stuart, R.K., Ramakrishnan, V., Wan, W., Peer, C.J., Dawson, J., Kang, L., Honeycutt, C., Tombes, M.B., Shrader, E., Weir-Wiggins, C., Wellons, M., Sankala, H., Hogan, K.T., Colevas, A.D., Doyle, L.A., Figg, W.D., Coppola, D., Roberts, J.D., Sullivan, D., Grant, S. Clin. Cancer Res. (2014) [Pubmed]
  28. Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Carlson, B., Lahusen, T., Singh, S., Loaiza-Perez, A., Worland, P.J., Pestell, R., Albanese, C., Sausville, E.A., Senderowicz, A.M. Cancer Res. (1999) [Pubmed]
  29. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Carlson, B.A., Dubay, M.M., Sausville, E.A., Brizuela, L., Worland, P.J. Cancer Res. (1996) [Pubmed]
  30. Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Melillo, G., Sausville, E.A., Cloud, K., Lahusen, T., Varesio, L., Senderowicz, A.M. Cancer Res. (1999) [Pubmed]
  31. Preclinical and clinical development of cyclin-dependent kinase modulators. Senderowicz, A.M., Sausville, E.A. J. Natl. Cancer Inst. (2000) [Pubmed]
  32. Combination therapy for adult T-cell leukemia-xenografted mice: flavopiridol and anti-CD25 monoclonal antibody. Zhang, M., Zhang, Z., Goldman, C.K., Janik, J., Waldmann, T.A. Blood (2005) [Pubmed]
  33. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. Schwartz, G.K., Ilson, D., Saltz, L., O'Reilly, E., Tong, W., Maslak, P., Werner, J., Perkins, P., Stoltz, M., Kelsen, D. J. Clin. Oncol. (2001) [Pubmed]
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