Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Abstract

Resting cells are relatively resistant to microtubule-active drugs including paclitaxel (PTX). By causing p53-mediated arrest, pretreatment with low concentrations of doxorubicin (DOX) protected HCT116 cells from the cytotoxicity caused by PTX. Unlike DOX, flavopiridol (FL) did not protect HCT116 cells. Low concentrations of FL (50 nM) induced p21 but not p53. High concentrations of FL (500 nM) decreased levels of p21 and Mdm-2 but dramatically induced p53. Thus, FL reciprocally affects p21 and p53. In LNCaP, a prostate cancer cell line which is highly sensitive to p21-induced growth arrest (p21-sensitive), low concentrations of FL (50 nM) induced p21 (without induction of p53) and caused G1 and G2 arrest. This precluded mitotic arrest, Bcl-2 and Raf-1 phosphorylation, and diminished cell death caused by PTX. In contrast, FL did not protect PC3M, arrest-resitant and highly aggressive prostate cancer cells. Like LNCaP, HL60 and SKBr3 cells are known to be p21-sensitive. As predicted, low concentrations of FL antagonized PTX-mediated cytotoxicity in HL60 and SKBr3 cell lines. In summary, only low concentrations of FL can induce p21, and, in turn, only p21-sensitive cells are protected from PTX.

Flavopiridol Induces Mitochondrial-Mediated Apoptosis in Murine Glioma GL261 Cells via Release of Cytochrome c and Apoptosis Inducing Factor

“…The down-regulation of p21 expression using a similar dose of flavopiridol treatment has also been reported for human prostate cell lines. 35 Since p21 has been shown to negatively regulate drug-induced changes in mitochondria, downregulation of its expression early after flavopiridol treatment would sensitize cells to undergo apoptosis. 22 Apoptosis still occurred despite the fact that p27 levels remained high over the 72 h interval of drug treatment.…”

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

“…70 Low concentrations of flavopiridol (40-50 nM) induce p21 and cause growth arrest in p21-hypersensitive cells (LNCaP, HL60, and SKBr3), protecting these cells from paclitaxel. 71 Unlike LNCaP cells, the highly autonomous PC3M cells were not protected from paclitaxel. 71 In human sarcoma cells, loss of Rb determines whether flavopiridol selectively sensitizes doxorubicin-induced cell killing.…”

“…71 Unlike LNCaP cells, the highly autonomous PC3M cells were not protected from paclitaxel. 71 In human sarcoma cells, loss of Rb determines whether flavopiridol selectively sensitizes doxorubicin-induced cell killing. 77 During tumor promotion and progression, 78 cancer cells lose sensitivity to transforming growth factor beta (TGFβ).…”

“…In each case the tumor cells were selectively killed. 66 Among inducers of a protective growth arrest, there are the CDK inhibitor p21, 67-70 the CDK inhibitor flavopiridol, 71 the PI-3K inhibitor LY294002, 43 a MEK inhibitor, 37 staurosporin, 56 and AG1451. 37 It has been shown, that p21, an inhibitor of CDKs, protects from cytotoxicity caused by paclitaxel, [67][68][69] suggesting that inhibitors of CDKs may predominantly protect cells that are sensitive to p21.…”

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

“…The CDK inhibitors are a large family of compounds and the vast majority of data obtained on hormone refractory prostate cancer has been from flavopiridol, a flavone that directly competes with ATP and inhibits multiple cyclin-dependent kinases. [73][74][75][76] Flavopiridol has been found in a number of pre-clinical studies to inhibit the growth or viability of many prostate cancer cell lines [77][78][79][80][81] and xenografts. 82 Clinical trials showed that flavopiridol has minimal activity as a monotherapy, 83 but may enhance radiation-induced cell death in prostate cancer cells, 84 and may act synergistically with taxanes to abrogate vascularity in transgenic mouse tumor models.…”