Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol

Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases (cdk s) and represents the first in this anticancer class to enter clinical tria ls. In anticipation of the likelihood that, as with other cancer drugs, acq uired resistance may limit the drug's efficacy, an acquired resistance mode l has been established by in vitro drug exposure of the human colon carcino ma cell line HCT116. This stably resistant line, possessing 8-fold resistan ce to flavopiridol, showed a lack of cross-resistance to the anticancer age nts etoposide, doxorubicin, paclitaxel, topotecan, and cisplatin, and notab ly to other chemical classes of cdk inhibitors: the aminopurines roscovitin e and purvalanol A, 9-nitropaullone, and hymenialdisine. Resistance did not seem to be related to differences in the levels of multidrug resistance dr ug efflux proteins, P-glycoprotein, and MRP1. Moreover, there were no chang es in overall drug accumulation between the resistant and sensitive cell li nes. Flavopiridol induced cell cycle arrest, apoptosis, and inhibition of r etinoblastoma gene product phosphorylation on serine 780 in both parental a nd resistant lines, but the latter required 8-fold higher concentrations to achieve these effects. Cyclin E protein levels and cyclin E-associated kin ase activity were increased in the resistant line, suggesting that overexpr ession of cyclin E may be the mechanism of resistance to flavopiridol. Howe ver, transfection of cyclin E to increase expression of this protein did no t result in an increase in resistance to flavopiridol. Thus, up-regulation of cyclin E alone does not seem to cause resistance to this cdk inhibitor.