Targeting Notch1 and proteasome as an effective strategy to suppress T-cell lymphoproliferative neoplasms
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Lujun Yang1,*, Shuangfeng Zhang1,*, Suraj Konnath George2, Rong Teng1, Xuefen You1, Mengqi Xu1, Hong Liu1, Xiaoping Sun3,4, Hesham M. Amin2,4, Wenyu Shi1,2
1Department of Hematology, Affiliated Hospital of the University of Nantong, Jiangsu 226001, China
2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
3Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
4The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, 77030, USA
*These authors have contributed equally to this work
Wenyu Shi, e-mail: [email protected]
Hesham M. Amin, e-mail: [email protected]
Keywords: T-cell lymphoproliferative neoplasms, Notch1, proteasome, γ-secretase inhibitors, bortezomib
Received: February 17, 2015 Accepted: March 14, 2015 Published: April 02, 2015
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.
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