title: HTLV-1-associated adult T cell leukemia is highly susceptible to Navitoclax due to enhanced Bax expression.
abstract: Over-expression of Bcl-2, Bcl-xL and Bcl-w is frequently associated with cancer resistance to chemotherapy. Navitoclax (ABT-263), an orally bio-available small-molecule mimetic of the Bcl-2 homology domain 3, specifically inhibits Bcl-2, Bcl-xL and Bcl-w. Despite promising results obtained from the clinical trials, the use of Navitoclax in patients is dose-limited due to induction of death of platelets via inhibition of Bcl-xL and subsequent thrombocytopenia. This side effect limits the use of Navitoclax in low doses and to very sensitive tumors. In this study, we show that HTLV-1-associated adult T-cell leukemia/lymphoma (ATL) cells, which over-express Bcl-2, Bcl-xL and Bcl-w, show a 10- to 20-fold higher sensitivity (EC50 = ∼ 25-50 nM) to Navitoclax compared to non-HTLV-1-associated leukemic cells (EC50 = ∼ 1 μM). Investigation of the molecular mechanisms revealed that the HTLV-1 oncogenic protein Tax up-regulates expression of the pro-apoptotic protein Bax which enhances the therapeutic efficacy of Navitoclax. In addition, we show that agents that inhibit the transcription elongation or translation initiation such as Wogonin and Roc-A can further decrease the effective dose of Navitoclax. Our study suggests that HTLV-1 ATL may be a good candidate disease for low dose Navitoclax therapy and probably with less risk of thrombocytopenia.
authors.affiliation: Medizinische Klinik V, Hematology, Oncology Und Rheumatology, University Heidelberg, Heidelberg, 69120, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Witzens-Harig
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany.
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000328:Adult; D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015490:HTLV-I Infections / Q000378:metabolism / Q000473:pathology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494826:BAX protein, human; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C528561:navitoclax
keywords: ABT-263; Bax; HTLV-1; Navitoclax; anti-cancer therapy