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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1220-1227.
Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-04-015149.
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Submitted April 5, 2006
Accepted August 23, 2006
Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)
Dharminder Chauhan, Paola Neri, Mugdha Velankar, Klaus Podar, Teru Hideshima, Mariateresa Fulciniti, Pierfrancesco Tassone, Noopur Raje, Constantine S. Mitsiades, Nicholas Mitsiades, Paul G. Richardson, Leigh Zawel, Mary Tran, Nikhil C. Munshi, and Kenneth C. Anderson*
Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Novartis Institute of Biomedical Research, Cambridge, MA, USA
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
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 (BMSCs) cells. 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 insulin-like 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 proteasome inhibitors Bortezomib and NPI-0052; as well as with conventional anti-MM agents melphalan or dexamethasone 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.
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