Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM).
Second mitochondria-derived activator of caspases (Smac) promotes apoptosis via activation of caspases. Here we show that a low-molecular-weight Smac mimetic LBW242 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib therapies. Examination of purified patient MM cells demonstrated similar results, without significant cytotoxicity against normal lymphocytes and bone marrow stromal cells (BMSCs). Importantly, LBW242 abrogates paracrine MM cell growth triggered by their adherence to BMSCs and overcomes MM cell growth and drug-resistance conferred by interleukin-6 or insulinlike growth factor-1. Overexpression of Bcl-2 similarly does not affect LBW242-induced cytotoxicity. Mechanistic studies show that LBW242-induced apoptosis in MM cells is associated with activation of caspase-8, caspase-9, and caspase-3, followed by PARP cleavage. In human MM xenograft mouse models, LBW242 is well tolerated, inhibits tumor growth, and prolongs survival. Importantly, combining LBW242 with novel agents, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the proteasome inhibitors bortezomib and NPI-0052, as well as with the conventional anti-MM agent melphalan, induces additive/synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating LBW242, alone and together with other anti-MM agents, to improve patient outcome in MM.
Chauhan
Dharminder
D
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Neri
Paola
P
Velankar
Mugdha
M
Podar
Klaus
K
Hideshima
Teru
T
Fulciniti
Mariateresa
M
Tassone
Pierfrancesco
P
Raje
Noopur
N
Mitsiades
Constantine
C
Mitsiades
Nicholas
N
Richardson
Paul
P
Zawel
Leigh
L
Tran
Mary
M
Munshi
Nikhil
N
Anderson
Kenneth C
KC
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004357:Drug Synergism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists*; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D024101:Mitochondrial Proteins / Q000819:agonists*; D018716:Molecular Mimicry; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology; D015996:Survival Rate; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D008558:Melphalan