Bepridil exhibits anti‐leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia |
| |
| Authors: | Patrizia Aureli Filomena De Falco Chiara Rompietti Daniele Sorcini Emanuela Varasano Debora Cecchini Tiziana Zei Ambra Di Tommaso Emanuela Rosati Gabriela Alexe Giovanni Roti Kimberly Stegmaier Mauro Di Ianni Franca Falzetti Paolo Sportoletti |
| |
| Affiliation: | 1. Institute of Hematology‐Centro di Ricerche Emato‐Oncologiche (CREO), University of Perugia, Perugia, Italy;2. Hematology Section, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy;3. Biosciences and Medical Embryology Section, Department of Experimental Medicine, University of Perugia, Perugia, Italy;4. Department of Pediatric Oncology, Dana‐Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA;5. Hematology and BMT Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy;6. Department of Medicine and Aging Sciences, University of Chieti Pescara, Chieti, Italy;7. Department of Hematology, Transfusion Medicine and Biotechnologies, Ospedale Civile, Pescara, Italy |
| |
| Abstract: | 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. |
| |
| Keywords: | NOTCH1 chronic lymphocytic leukemia targeted therapy |
|
|
