XK469, a novel antitumor agent, inhibits signaling by the MEK/MAPK signaling pathway

Cancer Chemotherapy and Pharmacology
Hong LinBen D Chen

Abstract

XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors including drug-resistant tumors. Previous studies have indicated that XK469 is an antiproliferative agent with a low cytotoxic effect in human H116 tumor cells. In this study, we sought to determine the signaling pathways involved in mediating its antiproliferative activity. The antiproliferative activity of XK469 was tested using human U-937 leukemia cells in culture. XK469-induced cell cycle arrest was determined using flow cytometric analysis. Phosphorylation/activation of MEK and MAPK was analyzed using immunoblot analyses with specific antibodies against p-MEK and p-MAPK. Cell cycle analysis revealed that XK469 arrested U-937 cells at the G(2)/M phase. Compared with conventional anticancer agents, XK469 showed very low, if any, cytotoxic or proapoptotic effect against U-937 cells. In contrast, treatment of U-937 cells with vinblastine, doxorubicin and m-AMSA resulted in extensive cell death through apoptotic pathways. XK469, but not other agents, potently inhibited the phosphorylation/activation of MEK in U-937 cells cultured in serum-containing medium. XK469 was also able to block the activation of MEK by serum addition in starve...Continue Reading

Citations

Nov 15, 2006·Investigational New Drugs·Amin M AlousiPatricia M LoRusso
May 26, 2009·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Wei Peng YongMark J Ratain
Sep 7, 2016·European Journal of Medicinal Chemistry·Qiao-Hong XiaXun Li

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