Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29508386
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Bepridil exhibits anti-leukemic activity associated with NOTCH1 pathway
inhibition in chronic lymphocytic leukemia
#MMPMID29508386
Baldoni S
; Del Papa B
; Dorillo E
; Aureli P
; De Falco F
; Rompietti C
; Sorcini D
; Varasano E
; Cecchini D
; Zei T
; Di Tommaso A
; Rosati E
; Alexe G
; Roti G
; Stegmaier K
; Di Ianni M
; Falzetti F
; Sportoletti P
Int J Cancer
2018[Aug]; 143
(4
): 958-970
PMID29508386
show ga
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.
free
free
free
