Multiple mechanisms contribute to the synergistic anti-myeloma activity of the pan-histone deacetylase inhibitor LBH589 and the rapalog RAD001

Leuk Res. 2014 Nov;38(11):1358-66. doi: 10.1016/j.leukres.2014.09.004. Epub 2014 Sep 28.

Abstract

We examined the pre-clinical activity of pan-histone deacetylase inhibitor LBH589 in combination with mTORC1 inhibitor RAD001 and observed that the drug combination strongly synergized in inducing cytotoxicity in multiple myeloma (MM) cells. LBH589 caused an increase in acetylated histones and RAD001 inhibited mTORC1 activity. RAD001 caused potent G0/G1 arrest while LBH589 induced pronounced apoptosis, both of which were enhanced when the drugs were used in combination. LBH589/RAD001 combination led to down regulation of pStat3, cyclins, CDKs and XIAP and up regulation of pro-apoptotic Bcl-2 family proteins. A clinical trial is underway using LBH589/RAD001 combination in relapsed MM patients.

Keywords: Apoptosis; Histone deacetylase inhibitor; Multiple myeloma; Proliferation; mTOR inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Synergism
  • Everolimus
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Indoles / pharmacology*
  • Multiple Myeloma / pathology*
  • Panobinostat
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • Tumor Microenvironment / drug effects

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Panobinostat
  • Everolimus
  • Sirolimus