Abstract
Bcl-2 family of proteins confers resistance to chemotherapy in multiple myeloma (MM). Identification of BH3-mimetic drugs that inactivate pro-survival targets by interfering with the interaction of Bcl-2 proteins may therefore be therapeutically useful. A recent study identify ABT-737, a potent small-molecule inhibitor of anti-apoptotic proteins Bcl-2, Bcl-xL, and Bcl-w with an affinity 2–3 orders of magnitude more potent than any previously reported compounds (
Nature
2005
, 435
:672
–681Chauhan et al.
); importantly, combining ABT-737 with Bortezomib would allow for the use of lower doses of Bortezomib. Another mechanism whereby MM cells evades the cytotoxic effects of chemotherapy is via p53 mutations. Bcl-2 is linked to p53-mediated signaling, and we therefore examined whether ABT-737 is able to overcome the tumorigenic effects conferred via p53 mutations. Co-precipitations experiments show that MM.1S cells (ABT-737-sensitive) predominantly carry wild type p53, whereas OPM-1 cell line (less sensitive to ABT-737) has mutant p53. Taken together, these finding suggest that 1) sensitivity to ABT-737 correlates with Bcl-2 expression in MM cells, 2) higher expression of Mcl-1 reduces sensitivity to ABT-737 whereas other anti-MM agents that block Mcl-1 may synergize with ABT-737, and 3) ABT-737 induces apoptosis in MM with p53 (wt) or p53 (mt), albeit with differential sensitivity. A report that ABT-737 enhances the apoptotic activity of chemotherapeutic agents (Cancer Cell
2005
, 8
:407
–419Olterdorf et al.
), together with our present findings, provides the framework for clinical trials of ABT-737, either alone or in combination with other anti-MM agents, to enhance efficacy, reduce toxicity, and overcome drug resistance in MM patients.Nature
2005
, 435
:672
–681Disclosure: No relevant conflicts of interest to declare.
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2006, The American Society of Hematology
2006
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