Promise of combining a Bcl-2 family inhibitor with bortezomib or SAHA for adult T-cell leukemia/lymphoma.

Background: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T- lymphocytes and its prognosis still remains very poor. Materials and Methods: The potential of combining the Bcl- 2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-X L , and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T- lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated. Results: ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1- Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti- apoptotic molecule that confers drug resistance on ATL cells. Conclusion: The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL. Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes associated with human T-cell lymphotropic virus type I (HTLV-1) (1, 2). The clinical subtypes of ATL have been divided into acute, lymphoma, chronic and smoldering (1), and a recent retrospective study showed that the median survival times of patients with these subtypes were 8.3, 10.6, 30.2 and 36.7 months and overall survival rates at 4 years were 11.4%, 16.2%, 35.0% and 43.2%, respectively (3). Novel therapeutic options such as allogeneic stem cell transplantation and anti- CCR4 monoclonal antibody have been recently introduced; however, the outcome of patients with ATL is still very poor and novel therapeutic approaches are urgently required. Members of the Bcl-2 family proteins are critical regulators of apoptosis and interactions between anti- apoptotic and pro-apoptotic members are the major determinants of cell death and survival. ABT-737 is a small molecule Bcl-2 homology 3 (BH3) mimetic that binds to surface hydrophobic grooves of anti-apoptotic Bcl-2 family members and has been shown to strongly and selectively inhibit Bcl-2, Bcl-X L and Bcl-w, but not Mcl-1 or A1. In preclinical studies, ABT-737 exhibited single-agent activity and also increased the sensitivities of malignant lymphoma and small cell lung carcinoma cell lines to chemotherapeutics (4, 5). ABT-263 (Navitoclax), an analogue of ABT-737, was also reported to be effective on various cancer-derived cell lines in vitro, in vivo animal model, and in several clinical trials (6-11). We previously demonstrated that Bcl-2 and Bcl- X L , as well as the Mcl-1 protein, were highly expressed in ATL cells and HTLV-1 infected T-cell lines. Fresh tumor cells derived from ATL patients were less sensitive to ABT- 737 than those derived from chronic lymphocytic leukemia (CLL) patients in vitro, however, ABT-737 synergistically