A Promising Therapeutic Implication of a Novel Bcl-2 Family Inhibitor ABT-737 for Adult T-Cell Leukemia/Lymphoma.

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell lymphotrophic virus type I. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATLL patients, but the treatment outcome of acute and lymphoma type ATLL remains very poor. Therefore, new therapeutic strategies are needed to improve patient outcome. Anti-apoptotic proteins, Bcl-2 and Bcl-XL have been reported to be highly expressed in ATLL cells, and confer resistance to chemotherapy. The aim of this study is to elucidate the therapeutic implication of ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a potent small-molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w for ATLL. We first examined the direct toxicity of ABT-737 against tumor cell lines in vitro. ABT-737 significantly inhibited growth of ATLL cell lines (MT-1, MT-2 and HuT102) and an acute T-cell leukemia cell line, Jurkat with IC50 values at 72h of 2.5μM, 0.4μM, 0.01μM and 0.75μM, respectively. In contrast, Burkitt lymphoma cell lines, Raji and Ramos were resistant to ABT-737 with IC50 values at 72h of 24μM and 7.0μM, respectively. Importantly, Bcl-2 protein was highly expressed in MT-1, MT-2, HuT102 and Jurkat cells, but not in Raji and Ramos cells. We next examined the mechanism of ABT-737 induced growth inhibition using MT-1 and MT-2 cells. ABT-737 induced apoptosis with cleavage of caspase 9 and caspase 3 without modulating cell cycle distribution. Furthermore, ABT-737 significantly induced apoptosis in fresh tumor cells obtained from ATLL patients. We finally elucidated the potential of ABT-737 to enhance the apoptosis induced by anti-Fas monoclonal antibody (mAb), and cytotoxicity induced by conventional chemotherapeutics. ABT-737 enhanced apoptosis induced by anti-Fas mAb in MT-1 and MT-2 cells. Most importantly, ABT-737 synergistically enhanced the cytotoxicity induced by either of doxorubicin, vincristine or etoposide. These results suggest that ABT-737, used either alone or in combination with other conventional cytotoxic drugs, represents a promising novel targeted approach to overcome drug resistance and improve patient outcome in ATLL.