A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma.
Bcl-2 or Bcl-X(L) confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w with markedly higher affinity than previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together, our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.
Chauhan
D
D
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Velankar
M
M
Brahmandam
M
M
Hideshima
T
T
Podar
K
K
Richardson
P
P
Schlossman
R
R
Ghobrial
I
I
Raje
N
N
Munshi
N
N
Anderson
K C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D001897:Boronic Acids / Q000633:toxicity; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D001713:Biphenyl Compounds; D001897:Boronic Acids; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013449:Sulfonamides; D051020:bcl-X Protein; D000069286:Bortezomib