Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of the novel Bcl-2 family inhibitor ABT-737.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-1). ABT-737, a small molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, significantly induced apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells, and synergistically enhanced the cytotoxicity and apoptosis induced by conventional cytotoxic drugs. Moreover, ABT-737 significantly inhibited the in vivo tumor growth of an ATLL mouse model. These results suggest that the use of an agent targeting anti-apoptotic bcl-2 family proteins, either alone or in combination with other conventional drugs, represents a novel promising approach for ATLL.

Ishitsuka K ，Kunami N ，Katsuya H ，Nogami R ，Ishikawa C ，Yotsumoto F ，Tanji H ，Mori N ，Takeshita M ，Miyamoto S ，Tamura K ... -  《-》

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

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor. 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. 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. The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL.

Kunami N ，Katsuya H ，Nogami R ，Ishitsuka K ，Tamura K ... -  《-》

A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.

Shoemaker AR ，Oleksijew A ，Bauch J ，Belli BA ，Borre T ，Bruncko M ，Deckwirth T ，Frost DJ ，Jarvis K ，Joseph MK ，Marsh K ，McClellan W ，Nellans H ，Ng S ，Nimmer P ，O'Connor JM ，Oltersdorf T ，Qing W ，Shen W ，Stavropoulos J ，Tahir SK ，Wang B ，Warner R ，Zhang H ，Fesik SW ，Rosenberg SH ，Elmore SW ... -  《-》

The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs.

High LM ，Szymanska B ，Wilczynska-Kalak U ，Barber N ，O'Brien R ，Khaw SL ，Vikstrom IB ，Roberts AW ，Lock RB ... -  《-》

The Bcl-2/Bcl-XL family inhibitor ABT-737 sensitizes ovarian cancer cells to carboplatin.

Witham J ，Valenti MR ，De-Haven-Brandon AK ，Vidot S ，Eccles SA ，Kaye SB ，Richardson A ... -  《CLINICAL CANCER RESEARCH》