nitrophenols and Leukemia-Lymphoma--Adult-T-Cell

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.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia-Lymphoma, Adult T-Cell; Nitrophenols; Piperazines; Proteasome Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Sulfonamides; Vorinostat

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.

Topics: Adult; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Biphenyl Compounds; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Female; Human T-lymphotropic virus 1; Humans; Immunohistochemistry; Jurkat Cells; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, SCID; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; T-Lymphocytes; Tumor Burden; Xenograft Model Antitumor Assays

Human T lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). ATLL is a severe malignancy with no effective treatment. HTLV-1 regulatory proteins Tax and HTLV-1 basic leucine zipper factor (HBZ) play a major role in ATLL development, by interfering with cellular functions such as CD4(+) T-cell survival. In this study, we observed that the expression of Bfl-1, an antiapoptotic protein of the Bcl-2 family, is restricted to HTLV-1-infected T-cell lines and to T-cells expressing both Tax and HBZ proteins. We showed that Tax-induced bfl-1 transcription through the canonical NF-κB pathway. Moreover, we demonstrated that Tax cooperated with c-Jun or JunD, but not JunB, transcription factors of the AP-1 family to stimulate bfl-1 gene activation. By contrast, HBZ inhibited c-Jun-induced bfl-1 gene activation, whereas it increased JunD-induced bfl-1 gene activation. We identified one NF-κB, targeted by RelA, c-Rel, RelB, p105/p50, and p100/p52, and two AP-1, targeted by both c-Jun and JunD, binding sites in the bfl-1 promoter of T-cells expressing both Tax and HBZ. Analyzing the potential role of antiapoptotic Bcl-2 proteins in HTLV-1-infected T-cell survival, we demonstrated that these cells are differentially sensitive to silencing of Bfl-1, Bcl-x(L), and Bcl-2. Indeed, both Bfl-1 and Bcl-x(L) knockdowns decreased the survival of HTLV-1-infected T-cell lines, although no cell death was observed after Bcl-2 knockdown. Furthermore, we demonstrated that Bfl-1 knockdown sensitizes HTLV-1-infected T-cells to ABT-737 or etoposide treatment. Our results directly implicate Bfl-1 and Bcl-x(L) in HTLV-1-infected T-cell survival and suggest that both Bfl-1 and Bcl-x(L) represent potential therapeutic targets for ATLL treatment.

Topics: Adult; Antineoplastic Agents, Phytogenic; Basic-Leucine Zipper Transcription Factors; bcl-X Protein; Biphenyl Compounds; CD4-Positive T-Lymphocytes; Cell Survival; DNA-Binding Proteins; Etoposide; Female; Gene Knockdown Techniques; Gene Products, tax; Genes, jun; HeLa Cells; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Ligases; Male; Minor Histocompatibility Antigens; NF-kappa B p50 Subunit; Nitrophenols; Nuclear Proteins; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Proto-Oncogene Proteins c-rel; Retroviridae Proteins; Sulfonamides; Transcription Factor RelB; Transcription, Genetic; Viral Proteins