Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells

Small molecule modulators of cyclin-dependent kinases for cancer therapy

“…Thus, the cyclin D1 transcriptional repression observed with avopiridol is consistent with the e ects of¯avopiridol on the mRNA expression of cell cycle genes from yeast cells (Gray et al, 1998) and may be a consequence of P-TEF (cdk9) related processes (Chao et al, 2000). In summary,¯avopiridol could induce cell cycle arrest by at least three di erent mechanisms: ®rst, by the direct inhibition of cdks; second, by preventing necessary threonine 160 phosphorylation of cdks due to inhibition of cdk7/cyclin H (Carlson et al, 1996a;Worland et al, 1993), and ®nally, by downregulation of cyclin D1 and cyclin D3, important cofactors for cdk4 and cdk6 activation (Figure 2).…”

“…To determine the e ects of¯avopiridol on cdks, studies utilizing puri®ed cdk's showed that¯avopiridol inhibits cdks 1, 2, 4 and 6 in a competitive manner with respect to ATP, with a Ki of 41 nM, with somewhat less potent e ect on cdk 7 (cdk-activating kinase) (Carlson et al, 1996a,b;Losiewicz et al, 1994;Singh et al, 1999;Worland et al, 1993). With the information obtained from the crystal structure of cdk2 and deschloro-¯avopiridol it became evident that avopiridol binds to the ATP binding pocket, with the benzopyran occupying the same region as the purine ring of ATP (De Azevedo et al, 1996), corroborating our prior biochemical studies with the compound (Carlson et al, 1996a,b;Losiewicz et al, 1994;Singh et al, 1999;Worland et al, 1993). Recently, Chao et al (2000) demonstrated that avopiridol inhibits P-TEF (Positive transcription elongation factor, also known as cdk9/cyclin T) in vitro with a Ki *3 nM.…”

Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells

“…It is worthy of note also that, at a partially inhibiting concentration, the Cdk inhibitors only reduce the rate of entry in S phase and of DNA replication, i.e. they produce eects similar to those reported earlier following either microinjection of anti-cyclin A (or anti-Cdk2) antibodies or transfection of a dominant negative Cdk2 and opposed to those resulting from an overexpression of cyclin E. Flavopiridol, a synthetic derivative of an alkaloid from the Indian plant Dysoxylum binectariferum (Sedlacek et al, 1996), is also a very potent inhibitor of Cdks, although somewhat less selective than roscovitine since it inhibits with similar ecacy in vitro Cdk1, 2, 4 and 7 (Worland et al, 1993). Because of its high toxicity on some cancer cells in vivo, it is a potentially promising anti-neoplastic agent already undergoing clinical trials.…”

Small-molecule cyclin-dependent kinase modulators

“…Initial studies with this flavonoid revealed clear evidence of G 1 /S or G 2 /M arrest, due to loss in cdk1 and cdk2 (Kaur et al, 1992;Worland et al, 1993;Losiewicz et al, 1994). Studies using purified cdks showed that the inhibition observed is reversible and competitively blocked by ATP, with a K i of 41 nm (Kaur Worland et al, 1993;Losiewicz et al, 1994;Carlson et al, 1996a, b).…”

“…Initial studies with this flavonoid revealed clear evidence of G 1 /S or G 2 /M arrest, due to loss in cdk1 and cdk2 (Kaur et al, 1992;Worland et al, 1993;Losiewicz et al, 1994). Studies using purified cdks showed that the inhibition observed is reversible and competitively blocked by ATP, with a K i of 41 nm (Kaur Worland et al, 1993;Losiewicz et al, 1994;Carlson et al, 1996a, b). Furthermore, the crystal structure of the complex of deschloroflavopiridol and cdk2 showed that flavopiridol binds to the ATP-binding pocket, with the benzopyran occupying the same region as the purine ring of ATP (De Azevedo et al, 1996), confirming the earlier biochemical studies with flavopiridol (Losiewicz et al, 1994).…”