HTLV-1-associated adult T cell leukemia is highly susceptible to Navitoclax due to enhanced Bax expression
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...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2016
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| In: |
International journal of cancer
Year: 2015, Volume: 138, Issue: 2, Pages: 507-514 |
| ISSN: | 1097-0215 |
| DOI: | 10.1002/ijc.29726 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/ijc.29726 Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.29726 
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| Author Notes: | Mathias Witzens‐Harig, Marco Giaisi, Rebecca Köhler, Peter H. Krammer and Min Li‐Weber |
| Summary: | 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. |
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| Item Description: | First published: 11 August 2015 Gesehen am 02.07.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1097-0215 |
| DOI: | 10.1002/ijc.29726 |