TY - JOUR
T1 - Synergistic cytotoxicity of busulfan, melphalan, gemcitabine, panobinostat, and bortezomib in lymphoma cells
AU - Teo, Esmeralda C.
AU - Valdez, Benigno C.
AU - Ji, Jie
AU - Li, Yang
AU - Liu, Yan
AU - Brammer, Jonathan E.
AU - Hosing, Chitra
AU - Nieto, Yago
AU - Champlin, Richard E.
AU - Andersson, Borje S.
N1 - Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients.
AB - DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients.
KW - Conditioning regimen
KW - lymphoma
KW - stem cell transplant
UR - http://www.scopus.com/inward/record.url?scp=84961218269&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961218269&partnerID=8YFLogxK
U2 - 10.3109/10428194.2016.1157871
DO - 10.3109/10428194.2016.1157871
M3 - Article
C2 - 26980288
AN - SCOPUS:84961218269
SN - 1042-8194
VL - 57
SP - 2644
EP - 2652
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 11
ER -