FLAVOPIRIDOL MEDIATES CELL-CYCLE ARREST AND APOPTOSIS IN ESOPHAGEAL CANCER-CELLS

Esophageal adenocarcinoma (SKGT-2, SKGT-4, and SKGT-5) and epidermoid carcinoma (HCE-4) cells containing variable retinoblastoma (Rb), cycli n D1, p16, and p53 expression patterns were exposed to the synthetic f lavone, flavopiridol. The IC50 was approximately 100-150 nM for each o f these cell lines. Exposure of esophageal carcinoma cells to 300 nM f lavopiridol induced cell cycle arrest and apoptosis, resulting in a 90 % inhibition of proliferation relative to that of nontreated cells aft er a 5-day exposure to the drug. Western blot analysis revealed diminu tion of cyclin D1, Rb, and p107 protein levels after flavopiridol expo sure. Whereas cell cycle arrest and overall growth inhibition did not correlate in any obvious manner with the genotype of these cell lines, apoptosis seemed to be more pronounced in SKGT-2 and SKGT-4 cells tha t lack Rb expression. Pretreatment of esophageal cancer cells with 9-c is-retinoic acid did not substantially potentiate flavopiridol activit y in these cell lines. Although the precise mechanism of flavopiridol- mediated cytotoxicity has not been fully defined, this drug is an attr active agent for molecular intervention in esophageal cancers and thei r precursor lesions; further evaluation of flavopiridol in this clinic al context is warranted.