NDLI: Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)

Content Provider	PubMed Central
Author	Chauhan, Dharminder Neri, Paola Velankar, Mugdha Podar, Klaus Hideshima, Teru Fulciniti, Mariateresa Tassone, Pierfrancesco Raje, Noopur Constantine, Mitsiades Nicholas, Mitsiades Richardson, Paul Leigh, Zawel Tran, Mary Munshi, Nikhil Anderson, Kenneth C.
Copyright Year	2007
Abstract	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.
Related Links	http://dx.doi.org/10.1182/blood-2006-04-015149
Ending Page	1227
Page Count	8
Starting Page	1220
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	3
Volume Number	109
Language	English
Publisher	American Society of Hematology
Publisher Date	2006-10-01
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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