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Bepridil exhibits anti‐leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia
Author(s) -
Baldoni Stefano,
Del Papa Beatrice,
Dorillo Erica,
Aureli Patrizia,
De Falco Filomena,
Rompietti Chiara,
Sorcini Daniele,
Varasano Emanuela,
Cecchini Debora,
Zei Tiziana,
Di Tommaso Ambra,
Rosati Emanuela,
Alexe Gabriela,
Roti Giovanni,
Stegmaier Kimberly,
Di Ianni Mauro,
Falzetti Franca,
Sportoletti Paolo
Publication year - 2018
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.31355
Subject(s) - bepridil , chronic lymphocytic leukemia , cancer research , apoptosis , leukemia , medicine , pharmacology , immunology , chemistry , calcium , biochemistry , verapamil
Dysregulated NOTCH1 signaling, by either gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression‐based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers. The antitumor efficacy of bepridil was associated with inhibition of NOTCH1 activity through a decrement in trans‐membrane and activated NOTCH1 protein levels with unchanged NOTCH2 protein levels. In a CLL xenotransplant model, bepridil significantly reduced the percentage of leukemic cells infiltrating the spleen via enhanced apoptosis and decreased NOTCH1 activation. In conclusion, we report in vitro and in vivo anti‐leukemic activity of bepridil associated with inhibition of the NOTCH1 pathway in CLL. These data provide a rationale for the clinical development of bepridil as anti‐NOTCH1 targeted therapy for CLL patients.