PURPOSE: XK469 (2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid), a synthetic quinoxaline phenoxypropionic acid derivative, has broad activity against murine tumors and is entering Phase I clinical development as a topoisomerase IIbeta inhibitor. This study investigated the underlying molecular 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 were studied in treated cells from the H460 lung cancer line and p21 and p53 knockout cells of the HCT 116 colon cancer line. RESULTS: XK469 arrested H460 cells at G(2)-M, which was associated with cdc2 phosphorylation and decreased cdc2 kinase activity. Moreover, XK469 stabilized p53 and subsequently increased p21(WAF1/CIP1). Furthermore, HCT116 p21(-/-) cells were less sensitive than wild-type cells to XK469-induced growth inhibition, but p53(+/+) and p53(-/-) cells were equally sensitive despite the absence of p21 induction in the p53(-/-) cells. CONCLUSIONS: When considered with published data, our study suggests a complex mechanism of XK469-mediated anticancer activity involving multiple pathways, including p53-dependent and -independent G(2)-M arrest via inactivation of cdc2-cyclin B1 kinase activity.
PURPOSE:XK469 (2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid), a synthetic quinoxalinephenoxypropionic acid derivative, has broad activity against murinetumors and is entering Phase I clinical development as a topoisomerase IIbeta inhibitor. This study investigated the underlying molecular 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 were studied in treated cells from the H460 lung cancer line and p21 and p53 knockout cells of the HCT 116 colon cancer line. RESULTS:XK469 arrested H460 cells at G(2)-M, which was associated with cdc2 phosphorylation and decreased cdc2 kinase activity. Moreover, XK469 stabilized p53 and subsequently increased p21(WAF1/CIP1). Furthermore, HCT116 p21(-/-) cells were less sensitive than wild-type cells to XK469-induced growth inhibition, but p53(+/+) and p53(-/-) cells were equally sensitive despite the absence of p21 induction in the p53(-/-) cells. CONCLUSIONS: When considered with published data, our study suggests a complex mechanism of XK469-mediated anticancer activity involving multiple pathways, including p53-dependent and -independent G(2)-M arrest via inactivation of cdc2-cyclin B1 kinase activity.
Authors: Nisha C Kakodkar; Radhika Peddinti; Morris Kletzel; Yufeng Tian; Lisa J Guerrero; Samir D Undevia; David Geary; Alexandre Chlenski; Qiwei Yang; Helen R Salwen; Susan L Cohn Journal: Pediatr Blood Cancer Date: 2011-01 Impact factor: 3.167
Authors: Wendy Stock; Samir D Undevia; Carol Bivins; Farhad Ravandi; Olatoyosi Odenike; Stefan Faderl; Elizabeth Rich; Gautam Borthakur; Lucy Godley; Srdan Verstovsek; Andrew Artz; William Wierda; Richard A Larson; Yanming Zhang; Jorge Cortes; Mark J Ratain; Francis J Giles Journal: Invest New Drugs Date: 2008-04-19 Impact factor: 3.850
Authors: Samir D Undevia; Federico Innocenti; Jacqueline Ramirez; Larry House; Apurva A Desai; Linda A Skoog; Deepti A Singh; Theodore Karrison; Hedy L Kindler; Mark J Ratain Journal: Eur J Cancer Date: 2008-07-21 Impact factor: 9.162