Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy

Sedlacek, Hans Harald; Czech, Jörg; Naik, Ramachandra; Kaur, Gurleen; Worland, Peter J.; Losiewicz, Michael D.; Parker, Bernard W.; Carlson, Brett L.; Smith, Alexis D.; Senderowicz, Adrian M.; Sausville, Edward A.

doi:10.3892/ijo.9.6.1143

Cited by 169 publications

(185 citation statements)

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“…But also inhibition of angiogenesis has been described (Fotsis et al, 1993). Finally, certain (iso)flavonoids, in particular the synthetic flavonoid flavopiridol, have been reported to be specific inhibitors of cyclin-dependent kinases Sedlacek, 1996). In this respect, flavopiridol is 250-fold more potent compared to genistein and quercetin .…”

Section: Discussionmentioning

confidence: 99%

“…The interest in these compounds is based on their biochemical activities, such as phosphotyrosine kinase inhibition (Akiyama et al, 1987;Glossmann et al, 1981), topoisomerase II inhibition (Markovits et al, 1989), and scavenging of free radicals (Bors et al, 1987;Cotelle et al, 1992). Recently, the synthetic compound flavopiridol has drawn considerable attention for its antiproliferative capacities as an inhibitor of cyclin-dependent kinases cdk1, cdk2, cdk4 and cdk7 (Sedlacek et al, 1996). Several phase 1 studies with flavopiridol are currently in progress (Senderowicz et al, 1998;Stinson et al, 1998), while several (iso)flavonoids have been reported to act as inhibitors of angiogenesis, implicating a potential role in the prevention as well as the treatment of cancer (Fotsis et al, 1993).…”

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confidence: 99%

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Potent interaction of flavopiridol with MRP1

et al. 1999

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The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its anti-proliferative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC 4 /ADR. The accumulation of daunorubicin in GLC 4 /ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 μ M . Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol. © 1999 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Potent interaction of flavopiridol with MRP1

et al. 1999

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“…Treatments of mononuclear cells from marrow aspirates of CLL patients led to inhibition of B-RAF, C-RAF, ERK and STAT3 phosphorylation in correlation with Mcl-1 downregulation and resulting in caspasedependent apoptosis (Fecteau et al 2011). Furthermore, flavopiridol, formerly L86-8275 or HMR 1275, is an hemisynthetic flavonoïd derivative from rohitukine, an alkaloid isolated from the Indian plant Dysoxylum binectariferum (Sedlacek et al 1996). Flavopiridol was first described as a cyclin-dependent kinase inhibitor .…”

Section: Leukemiamentioning

confidence: 99%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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“…All other Cdk inhibitors are mainly synthetic compounds. Flavopiridol, an alkaloid derivative and member of the flavone group, displayed antiproliferative and cytotoxic effects on tumor cells at nanomolar concentrations (Sedlacek et al, 1996). This observation was associated with cell cycle arrest through inhibition of Cdk and induction of apoptosis in human hematopoietic cell lines, breast, lung, as well as head and neck squamous cell carcinoma (Kaur et al, 1992;Konig et al, 1997;Parker et al, 1998;Patel et al, 1998).…”

Section: Overview Of Small Molecule Cdk Inhibitors: Selectivity and Mmentioning

confidence: 99%

“…This observation was associated with cell cycle arrest through inhibition of Cdk and induction of apoptosis in human hematopoietic cell lines, breast, lung, as well as head and neck squamous cell carcinoma (Kaur et al, 1992;Konig et al, 1997;Parker et al, 1998;Patel et al, 1998). In spite of inconsistent data of IC 50 and K d values for different Cdk, flavopiridol showed high affinity to all Cdk with IC 50 values below 400 nM and exhibit higher selectivity to Cdk9 (IC 50 < 10 nM) (Chao et al, 2000;Sedlacek, 2001;Sedlacek, 1996). Cdk9, as well as Cdk7 inhibition lead to profound influence on cellular transcription, e. g., on mRNA transcripts for cell cycle regulators Cyclin D, antiapoptotic proteins Bcl-2 and Mcl-2, and NFB as well as p53 pathway (Lam et al, 2001;Lu et al, 2004).…”

Section: Overview Of Small Molecule Cdk Inhibitors: Selectivity and Mmentioning

confidence: 99%