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

Cancer Chemother Pharmacol. 2002 Apr;49(4):281-6. doi: 10.1007/s00280-002-0425-7. Epub 2002 Jan 24.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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


  • 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