A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma

Abstract

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.

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

“…Inactivation of Bcl-2 or Bcl-x L alone may not be sufficient to counteract resistance to proteasome inhibitors. In this context, our results provide a molecular explanation for the only modest enhancement of bortezomib-induced cell death with the BH3 mimetics, ABT-737 22 and BH3I-2 0 , 40 which bind poorly to Mcl-1. Conversely, (À)-gossypol and other BH3 mimetics with high affinity for Mcl-1 and Bcl-x L can dismantle the protective shield that halts caspase activation in melanoma cells.…”

“…21 Unfortunately, ABT-737 had a relatively modest effect on the cytotoxicity of bortezomib (1.3-fold induction of cell death). 22 A likely explanation for this limited cooperation is that ABT-737 has a high affinity for Bcl-2 and Bcl-x L , but binds poorly to Mcl-1, 21 which is induced by bortezomib. Broader spectrum antagonists of antiapoptotic Bcl-2 proteins are being investigated (reviewed by Zhai et al 20 ).…”

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

“…The basal expression level of Mcl-1, to which ABT-737 has a low affinity, has been associated with resistance to ABT-737 in AML (20), lymphoma (23), CLL (25), and many other cancer types (22,26,46). ABT-737 was less efficient in killing tumor cells exhibiting relatively high levels of Mcl-1 (47), and downregulation of Mcl-1 was observed in cancer cell sensitization to ABT-737.…”

“…Gemcitabine has been widely used for patients with relapsed or refractory solid tumors, especially when combined with chemotherapeutic agents (40)(41)(42)(43), aiming to improve the anticancer efficiency with lower toxicity. Downregulation of Mcl-1 was observed with treatments of gemcitabine combined with other chemotherapeutic agents, thus the combination of gemcitabine (Mcl-1-downregulating agents) with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant solid tumors (22).…”

“…ABT-737 has shown preclinical anticancer activity as a single agent or in combination with other chemotherapeutic agents against acute myeloid leukemia (AML; refs. 20,21), multiple myeloma (22), lymphoma (23,24), chronic lymphocytic leukemia (25), small-cell lung cancer (19,26), head and neck squamous cancer (27), and acute lymphoblastic leukemia (1,28). Given that ABT-737 binds to Mcl-1 with low affinity, the high basal expressions of Mcl-1 in small-cell lung cancer cells (29,30) and in other types of cancer cells (19,31) have been validated to associate with the resistance to ABT-737 (24).…”