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

Abstract

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-XL, 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.

Keywords: ABT-737; Adult T-cell leukemia/lymphoma; Bcl-2 family protein; bortezomib; suberoylanilide hydroxamic acid.