TY - JOUR
T1 - Targeting Notch1 and proteasome as an effective strategy to suppress T-cell lymphoproliferative neoplasms
AU - Yang, Lujun
AU - Zhang, Shuangfeng
AU - George, Suraj Konnath
AU - Teng, Rong
AU - You, Xuefen
AU - Xu, Mengqi
AU - Liu, Hong
AU - Sun, Xiaoping
AU - Amin, Hesham M.
AU - Shi, Wenyu
PY - 2015
Y1 - 2015
N2 - The T-cell lymphoproliferative neoplasms (T-LPN) are characterized by a poor clinical outcome. Current therapeutics are mostly non-selective and may induce harmful side effects. It has been reported that NOTCH1 activation mutations frequently associate T-LPN. Because anti-Notch1 based therapies such as γ-secretase inhibitors (GSI) are less efficient and induce considerable side effects, we hypothesized that combining low concentrations of GSI and the proteasome inhibitor bortezomib (BTZ) may provide an effective and tolerable approach to treat T-LPN. Hence, we analyzed the in vitro and in vivo effects of GSI-I and BTZ, alone or in combination, against T-LPN. GSI-I and BTZ synergistically decreased cell viability, proliferation, and colony formation, and induced apoptosis in T-LPN cell lines. Furthermore, combining GSI-I and BTZ decreased the viability of primary T-LPN cells from patients. These effects were accompanied by deregulation of Notch1, AKT, ERK, JNK, p38 MAPK, and NF-κB survival pathways. Moreover, combination treatment inhibited T-LPN tumor growth in nude mice. In all experiments, combining low concentrations of GSI-I and BTZ was superior to using a single agent. Our data support that a synergistic antitumor activity exists between GSI-I and BTZ, and provide a rationale for successful utilization of dual Notch1 and proteasome inhibition to treat T-LPN.
AB - The T-cell lymphoproliferative neoplasms (T-LPN) are characterized by a poor clinical outcome. Current therapeutics are mostly non-selective and may induce harmful side effects. It has been reported that NOTCH1 activation mutations frequently associate T-LPN. Because anti-Notch1 based therapies such as γ-secretase inhibitors (GSI) are less efficient and induce considerable side effects, we hypothesized that combining low concentrations of GSI and the proteasome inhibitor bortezomib (BTZ) may provide an effective and tolerable approach to treat T-LPN. Hence, we analyzed the in vitro and in vivo effects of GSI-I and BTZ, alone or in combination, against T-LPN. GSI-I and BTZ synergistically decreased cell viability, proliferation, and colony formation, and induced apoptosis in T-LPN cell lines. Furthermore, combining GSI-I and BTZ decreased the viability of primary T-LPN cells from patients. These effects were accompanied by deregulation of Notch1, AKT, ERK, JNK, p38 MAPK, and NF-κB survival pathways. Moreover, combination treatment inhibited T-LPN tumor growth in nude mice. In all experiments, combining low concentrations of GSI-I and BTZ was superior to using a single agent. Our data support that a synergistic antitumor activity exists between GSI-I and BTZ, and provide a rationale for successful utilization of dual Notch1 and proteasome inhibition to treat T-LPN.
KW - Bortezomib
KW - Notch1
KW - Proteasome
KW - T-cell lymphoproliferative neoplasms
KW - γ-secretase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84934300730&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84934300730&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3621
DO - 10.18632/oncotarget.3621
M3 - Article
C2 - 25879451
AN - SCOPUS:84934300730
SN - 1949-2553
VL - 6
SP - 14953
EP - 14969
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -