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.
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.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Sampath
S
Ramachandiran
Joan
J
Cain
Albert
A
Liao
Yanjuan
Y
He
Xiangxue
X
Guo
Lawrence H
LH
Boise
Haian
H
Fu
Lee
L
Ratner
Hanna Jean
HJ
Khoury
Leon
L
Bernal-Mizrachi
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D032701:Biomimetics; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D006800:Deltaretrovirus Infections / Q000150:complications; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D020031:Epstein-Barr Virus Infections / Q000150:complications; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D004151:Dipeptides; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C572769:RMT5265; D013777:Tetrazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; D045304:Cytochromes c