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.