MJ-29 Inhibits Tubulin Polymerization and Induces Apoptosis in Human Leukemia Cells

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Researchers in Taichung, Taiwan, have investigated the signaling pathways associated with microtubule interaction and apoptosis in human leukemia U937 cells. They used 6-pyrrolidinyl-2-(2-hydroxyphenyl)-4-quinazolinone (MJ-29) to induce growth inhibition and cell death in leukemia cell lines. The study found that MJ-29 interacted with alpha-and beta-tubulin, inhibited tubulin polymerization, and disrupted microtubule organization. MJ-29 also caused mitotic arrest by activating cyclin-dependent kinase 1 (CDK1)/cyclin B complex activity.

Key Takeaways:

  • MJ-29 inhibited tubulin polymerization and induced mitotic arrest in human leukemia U937 cells.
  • MJ-29 interacted with alpha-and beta-tubulin and disrupted microtubule organization.
  • MJ-29 caused an increase in the protein levels of cytosolic cytochrome c, apoptotic protease-activating factor-1, procaspase-9, and apoptosis-inducing factor.
  • MJ-29-promoted activation of caspase-9 and caspase-3 during apoptosis was significantly attenuated by caspase-9 and caspase-3 inhibitors.
  • MJ-29 inhibited tumor growth in vivo in BALB/c(nu/nu) mice bearing U937 xenograft tumors.
  • The terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling-positive apoptotic cells of tumor sections significantly increased in MJ-29-treated mice compared with the control group.

Statistics:

  • 4 leukemia cell lines (U937, HL-60, K562, and KG-1) were used in the study.
  • MJ-29 inhibited cells in a dose-and time-dependent manner.
  • Peripheral blood mononucleated cells and human umbilical vein endothelial cells were used as normal cell controls.
  • The study found a significant increase in the protein levels of cytosolic cytochrome c, apoptotic protease-activating factor-1, procaspase-9, and apoptosis-inducing factor in MJ-29-treated cells.
  • Caspase-9 and caspase-3 activation was significantly attenuated by caspase inhibitors.
  • Tumor growth in vivo in MJ-29-treated mice was inhibited by 30% compared to the control group.

Sources:

  • Yang, J.S., et al. "MJ-29 inhibits tubulin polymerization, induces mitotic arrest, and triggers apoptosis via cyclin-dependent kinase 1-mediated Bcl-2 phosphorylation in human leukemia U937 cells." Journal of Pharmacology and Experimental Therapeutics, 2010; 334(2): 477-88.
  • Proline-Directed Protein Kinases.