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: Mathias Witzens-Harig, Marco Giaisi, Rebecca Köhler, Peter H Krammer, Min Li-Weber
• Journal: International journal of cancer (Int J Cancer) Vol. 138 Issue 2 Pg. 507-14 (Jan 15 2016) ISSN: 1097-0215 [Electronic] United States
• PMID: 26260669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 UICC.

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• BAX protein, human
• Sulfonamides
• bcl-2-Associated X Protein
• navitoclax

Topics

• Adult
• Aniline Compounds (pharmacology)
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• HTLV-I Infections (metabolism, pathology)
• Human T-lymphotropic virus 1
• Humans
• Leukemia-Lymphoma, Adult T-Cell (metabolism, pathology, virology)
• Sulfonamides (pharmacology)
• Transfection
• bcl-2-Associated X Protein (biosynthesis)