Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells.

E7070 is a novel sulfonamide antitumoragent that exhibits potent antitumoractivity in vitro and in vivo.This compound affects cell cycleprogression in human tumor cells. Toelucidate the mechanisms by which E7070inhibits tumor cell growth, we establishedand characterized an E7070-resistantsubline, A549/ER, from a human non-smallcell lung cancer cell line A549. Flowcytometric analyses demonstrated anincrease in G0/G1 and a decrease in S phasepopulations in cells treated with E7070 at20 or 100 μg/ml for 24 h. Longerexposure to E7070, i.e. 48 and 72 h,increased the G2/M phase fraction in A549cells. These inhibitory actions of E7070on cell cycle progression were not observedin A549/ER cells. E7070 inhibited thephosphorylation of pRb, decreasedexpressions of cyclin A, B1, CDK2, and CDC2proteins, and suppressed CDK2 catalyticactivity with the induction of p53 andp21 proteins in A549 cells but not inA549/ER cells. Taken together, theseresults suggest that E7070 exerts itsantitumor effects by disturbing the cellcycle at multiple points, including boththe G1/S and the G2/M transition, in humanlung cancer cells.