In vitro evaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer

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Abstract
Purpose: To determine the in vitro effects of flavopiridol on bladder cancer cell lines, immortalized urothelial cell lines, and normal urothelial cells well characterized for defects in p53, pRb, and p16. Methods: Growth inhibition was assessed via an MTT assay and apoptosis via DAPI nuclear staining. Cell cycle analysis was performed via propidium iodide staining and fluorescent activated cell sorting (FACS). Multidrug-resistant cells were generated by continuous exposure to doxorubicin. Results: Growth inhibition was not correlated with inactivation of p53, pRb, or p16. All cells experienced G2/M arrest within 24 h of flavopiridol exposure. Modest apoptosis was observed but required 72 h of continuous drug exposure to become evident. There was no obvious synergistic or antagonistic toxicity when flavopiridol was combined with radiotherapy or cisplatin dosed at the IC50 despite the observation that radiotherapy and flavopiridol led to more profound G2/M arrest than either agent alone. Doxorubicin-resistant cells, demonstrated to overexpress the MDR1 multidrug-resistance protein were equally as sensitive to flavopiridol as the parental cells. Conclusions: Flavopiridol is a novel cell cycle inhibitor that may be a useful agent in bladder cancers with tumor suppressor gene alterations and/or multidrug resistance.

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