HTLV-1-associated adult T cell leukemia is highly susceptible to Navitoclax due to enhanced Bax expression

• Verfasst von: Witzens-Harig, Mathias [VerfasserIn]
• Verfasst von: Giaisi, Marco [VerfasserIn]
• Verfasst von: Köhler, Rebecca [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Li-Weber, Min [VerfasserIn]
• Titel: HTLV-1-associated adult T cell leukemia is highly susceptible to Navitoclax due to enhanced Bax expression
• Verf.angabe: Mathias Witzens‐Harig, Marco Giaisi, Rebecca Köhler, Peter H. Krammer and Min Li‐Weber
• Jahr: 2016
• Jahr des Originals: 2015
• Umfang: 8 S.
• Teil: volume:138
• Teil: year:2016
• Teil: number:2
• Teil: pages:507-514
• Teil: extent:8
• Fussnoten: First published: 11 August 2015 ; Gesehen am 02.07.2020
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2016
• Band/Heft Quelle: 138(2016), 2, Seite 507-514
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.29726
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ABT-263
• Sach-SW: anti-cancer therapy
• Sach-SW: Bax
• Sach-SW: HTLV-1
• Sach-SW: Navitoclax
• K10plus-PPN: 1703397460

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.