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

Mathias Witzens-Harig, Marco Giaisi, Rebecca Köhler, Peter H. Krammer, Min Li-Weber

    Research output: Contribution to journalArticle

    3 Scopus citations

    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. What's new? The novel small molecule navitoclax selectively targets Bcl-2, Bcl-xL and Bcl-w, making it a potent inducer of apoptosis. A major obstacle in navitoclax therapy, however, is thrombocytopenia, which limits its use to only highly sensitive tumors. This study shows that HTLV-1-infected adult T-cell leukemia/lymphoma (ATL) cells are more sensitive to Navitoclax than non-HTLV-1-associated cells. Increased sensitivity was attributed to HTLV-1 Tax-mediated overexpression of the pro-apoptotic protein Bax. In addition to specific targeting of Navitoclax-sensitive HTLV-1-associated cells, Mcl-1 down-regulation via inhibition of transcription elongation or translation initiation may allow for a further decrease in Navitoclax dose, lowering thrombocytopenia risk.

    Original languageEnglish (US)
    Pages (from-to)507-514
    Number of pages8
    JournalInternational Journal of Cancer
    Volume138
    Issue number2
    DOIs
    StatePublished - Jan 15 2016

    Keywords

    • ABT-263
    • Bax
    • HTLV-1
    • Navitoclax
    • anti-cancer therapy

    ASJC Scopus subject areas

    • Medicine(all)
    • Oncology
    • Cancer Research

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