Effects of hippuristanol, an inhibitor of eIF4A, on adult T-cell leukemia

Biochem Pharmacol. 2011 Mar 15;81(6):713-22. doi: 10.1016/j.bcp.2010.12.025. Epub 2011 Jan 8.

Abstract

We evaluated the anti-adult T-cell leukemia (ATL) effects of hippuristanol, an eukaryotic translation initiation inhibitor from the coral Isis hippuris. Hippuristanol inhibited proliferation of HTLV-1-infected T-cell lines and ATL cells, but not normal peripheral blood mononuclear cells. It induced cell cycle arrest during G₁ phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and induced apoptosis by reducing the expression of Bcl-x(L), c-IAP2, XIAP and c-FLIP. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Hippuristanol also suppressed IkappaBalpha phosphorylation and depleted IKKalpha, IKKgamma, JunB and JunD, resulting in inactivation of NF-kappaB and AP-1. It also suppressed carbonic anhydrase type II expression. In addition to its in vitro effects, hippuristanol suppressed tumor growth in mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells. These preclinical data suggest that hippuristanol could be a potentially useful therapeutic agent for patients with ATL.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cells, Cultured
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • DEAD-box RNA Helicases / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Eukaryotic Initiation Factor-4A
  • Female
  • Human T-lymphotropic virus 1 / drug effects
  • Human T-lymphotropic virus 1 / physiology
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / drug therapy*
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Mice
  • Mice, Inbred ICR
  • Mice, SCID
  • Sterols / pharmacology*
  • Sterols / therapeutic use

Substances

  • Enzyme Inhibitors
  • Sterols
  • hippuristanol
  • Eukaryotic Initiation Factor-4A
  • EIF4A3 protein, human
  • DEAD-box RNA Helicases