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HTLV‐1‐associated adult T cell leukemia is highly susceptible to N avitoclax due to enhanced B ax expression
Author(s) -
WitzensHarig Mathias,
Giaisi Marco,
Köhler Rebecca,
Krammer Peter H.,
LiWeber Min
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29726
Subject(s) - t cell leukemia , leukemia , cancer research , microbiology and biotechnology , apoptosis , lymphoma , t cell , biology , virology , immunology , chemistry , immune system , biochemistry
Over‐expression of Bcl‐2, Bcl‐x L 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‐x L 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‐x L 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 (EC 50 = ∼25–50 nM) to Navitoclax compared to non‐HTLV‐1‐associated leukemic cells (EC 50 = ∼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.