The Smac mimetic RMT5265.2HCL induces apoptosis in EBV and HTLV-I associated lymphoma cells by inhibiting XIAP and promoting the mitochondrial release of cytochrome C and Smac

Leuk Res. 2012 Jun;36(6):784-90. doi: 10.1016/j.leukres.2011.12.024. Epub 2012 Feb 10.

Abstract

The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Biomimetics*
  • Cell Line, Tumor
  • Cell Transformation, Viral / drug effects
  • Cytochromes c / metabolism
  • Deltaretrovirus Infections / complications
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Epstein-Barr Virus Infections / complications
  • HEK293 Cells
  • Herpesvirus 4, Human / physiology
  • Human T-lymphotropic virus 1 / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins* / chemistry
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Lymphoma, T-Cell / drug therapy
  • Lymphoma, T-Cell / etiology
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology*
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Proteins* / chemistry
  • Mitochondrial Proteins* / metabolism
  • Models, Biological
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*
  • Up-Regulation / drug effects
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Dipeptides
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • RMT5265
  • Tetrazoles
  • X-Linked Inhibitor of Apoptosis Protein
  • Cytochromes c