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

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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 starved U-937 cells. Exposure of cells to XK469 for 1 h was sufficient to inhibit the activation of MEK and its downstream kinase, MAPK. The antiproliferative response to XK469 was correlated with a steady accumulation of cyclins B1 and A, which appeared to be a direct result of G(2)/M arrest.

CONCLUSIONS:

Our findings suggest that the antiproliferative effect of XK469 is mediated by inhibiting the MEK/MAPK signaling pathways in U-937 human leukemia cells.

• Authors: Hong Lin, Balanehru Subramanian, Alex Nakeff, Ben D Chen
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 49 Issue 4 Pg. 281-6 (Apr 2002) ISSN: 0344-5704 [Print] Germany
• PMID: 11914906 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• CCNB1 protein, human
• Cyclin B
• Cyclin B1
• Enzyme Inhibitors
• Quinoxalines
• Tumor Suppressor Protein p53
• XK 469
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 1
• MAP3K1 protein, human

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Cyclin B (metabolism)
• Cyclin B1
• Enzyme Inhibitors (pharmacology)
• G2 Phase (drug effects)
• Humans
• MAP Kinase Kinase Kinase 1
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Mitosis (drug effects)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Quinoxalines (pharmacology)
• Tumor Suppressor Protein p53 (physiology)