The investigational new drug XK469 induces G(2)-M cell cycle arrest by p53-dependent and -independent pathways

Purpose: XK469 {2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid}, a synthetic quinoxaline phenoxypropionic acid derivative, has broad activit y against murine tumors and is entering Phase I clinical development as a t opoisomerase II beta inhibitor. This study investigated the underlying mole cular mechanism of XK469's effects on the cell cycle. Experimental Design: Growth inhibition, cell cycle arrest, induction of p53 and p21 mRNA and protein, and cdc2 phosphorylation and kinase activity wer e studied in treated cells from the H460 lung cancer line and p2l and p53 k nockout cells of the HCT 116 colon cancer line. Results: XK469 arrested H460 cells at G(2)-M, which was associated with cdc 2 phosphorylation and decreased cdc2 kinase activity. Moreover, XK469 stabi lized p53 and subsequently increased p21(WAF1/CIP1). Furthermore, HCT116 p2 1(-/-) cells were less sensitive than wild-type cells to XK469-induced grow th inhibition, but p53(+/+) and p53(-/-) cells were equally sensitive despi te the absence of p2l induction in the p53(-/-) cells. Conclusions: When considered with published data, our study suggests a comp lex mechanism of XK469-mediated anticancer activity involving multiple path ways, including p53-dependent and -independent G(2)-M arrest via inactivati on of cdc2-cyclin B1 kinase activity.