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

Ramachandiran, Sampath; Cain, Joan; Liao, Albert; He, Yanjuan; Guo, Xiangxue; Boise, Lawrence H.; Fu, Haian; Ratner, Lee; Khoury, Hanna Jean; Bernal-Mizrachi, Leon

doi:10.1016/j.leukres.2011.12.024

« Previous Next »Leukemia Research
Volume 36, Issue 6 , Pages 784-790, June 2012

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

Sampath Ramachandiran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Joan Cain
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Albert Liao
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Yanjuan He
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Xiangxue Guo
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Lawrence H. Boise
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Haian Fu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
- Department of Pharmacology, Emory University, Atlanta, GA, USA
Lee Ratner
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
Hanna Jean Khoury
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
Leon Bernal-Mizrachi
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
- Corresponding author at: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Road, Room C1152B, Atlanta, GA 30322, USA. Tel.: +1 404 778 1670; fax: +1 404 778 4755.

Received 24 October 2011; received in revised form 29 December 2011; accepted 30 December 2011. published online 13 February 2012.

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.

Keywords: XIAP, EBV, HTLV-1, HHV-8, Lymphomas, Smac mimetics