Mitochondrial signaling is an important component of chemotherapy-induced apoptosis in cancer cells (

Korsmeyer, SJ, 2004 Cell, 111:205–219
). Members of the Bcl-2 family of proteins regulate, in part, the release of apoptogenic factors, such as cytochrome-c from the intermembrane space into the cytosol, thereby initiating caspase-9-mediated cell-death signaling cascade (Reed, SJ 1997, 34: 9–19;
Kirkin et al, 2004, Biochim Biophys Acta. 2204, 1644:229–249
). Overexpression of Bcl-2 or Bcl-x(L) confers resistance to chemotherapy in cancer cells, including MM (
Letai, A 2004 Cancer cell, 6:241–249
;
Chauhan et al, 2005, Annu Rev Pharmocol Toxicol, 45:465–476
). Here we utilized ABT-737 (Abbott Laboratories), a potent small-molecule inhibitor of anti-apoptotic proteins Bcl-2, Bcl-x(L) and Bcl-w with markedly higher affinity than previously reported compounds (
Oltersdorf, Elmore, &Shoemaker et al, Nature 2005, 435; 677–81
). We show that ABT-737 inhibits the growth of MM cells, including those resistant to conventional agents dexamethasone, melphalan or doxorubicin. Examination of purified patient MM cells demonstrated similar results. Importantly, ABT-737 also decreases the viability of CD138+ tumor cells obtained from Bortezomib-refractory MM patient. In contrast, no significant toxicity of ABT-737 was observed against peripheral blood mononuclear cells from normal healthy donors or CD138− MM patient cells. Moreover, ABT-737 does not affect the viability of MM patient-derived bone marrow stromal cells (BMSCs). Mechanistic studies show that ABT-737-triggered apoptosis in MM cells is associated with activation of caspase-8, caspase-9, and caspase-3, followed by proteolytic cleavage of poly (ADP) ribose (PARP) enzyme. Finally, ABT-737 enhances the anti-MM activity of Bortezomib or Melphalan, without significant toxicity in normal cells. Collectively, these findings provide the rationale for clinical evaluation of ABT-737 alone, or in combination with Bortezomib or Melphalan, to enhance MM cell killing, overcome drug-resistance, and improve patient outcome in MM.

Topics:
abt-737, bcl2 gene, bortezomib, caspase-3, caspase-8, caspase-9, caspases, chemotherapy regimen, cytochrome c, dexamethasone

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2005, The American Society of Hematology
2005
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