RT Journal Article
SR Electronic
T1 Promise of Combining a Bcl-2 Family Inhibitor with Bortezomib or SAHA for Adult T-cell Leukemia/Lymphoma
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 5287
OP 5294
VO 34
IS 10
A1 NAOKO KUNAMI
A1 HIROO KATSUYA
A1 RUMIKO NOGAMI
A1 KENJI ISHITSUKA
A1 KAZUO TAMURA
YR 2014
UL http://ar.iiarjournals.org/content/34/10/5287.abstract
AB 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.