TY - JOUR
T1 - Targeted therapy for EBV-associated B-cell neoplasms
AU - Ganguly, Siddhartha
AU - Kuravi, Sudhakiranmayi
AU - Alleboina, Satyanarayana
AU - Mudduluru, Giridhar
AU - Jensen, Roy A.
AU - McGuirk, Joseph P.
AU - Balusu, Ramesh
N1 - Funding Information:
S. Ganguly has received speakers bureau honoraria from Seattle Genetics and is a consultant/advisory board member for Amgen, Takeda, Janssen, Kite Pharma, and Daiichi Sankyo. J.P. McGuirk reports receiving commercial research grants from Novartis, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, and Pluristem Ltd, reports receiving other commercial research support from ArticulateScience LLC, and has received speakers bureau honoraria from Kite Pharma. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors would like to thank Ms. Sophia McCormick and Mrs. Cassaundra Shipman from the Biospecimen Repository Core Facility (BRCF), the University of Kansas Medical Center (Kansas City, KS) for providing healthy donor blood to isolate normal B cells. R. Balusu acknowledges the pilot award from American Cancer Society (ACS-IRG-16-194-07), Sosland Family Foundation Research Award, Hale Family Foundation, and Frontiers Clinical and Translational Pilot AwardUL1TR000001.WeareverygratefultoDr.JaniceCheng(labmember)for thorough proofreading of the manuscript.
Publisher Copyright:
© 2019 Society of Materials Science Japan.All right reserved.
PY - 2019
Y1 - 2019
N2 - Epstein-Barr virus (EBV) is directly implicated in several B-cell lymphoid malignancies. EBV-associated lymphomas are characterized by prominent activation of the NF-kB pathway and targeting this pathway establishes a rationale for a therapeutic approach. The ubiquitin/proteasome signaling plays an essential role in the regulation of the NF-kB pathway. Ixazomib is an FDAapproved, orally bioavailable proteasome inhibitor. Here we report the first preclinical evaluation of ixazomibmediated growth-inhibitory effects on EBV-infected B-lymphoblastoid cell lines Raji and Daudi. Ixazomib induced apoptosis in these cell lines in a dosedependent manner. Cell-cycle analysis demonstrated ixazomib treatment induced cell-cycle arrest at the G2-M phase with a concomitant decrease in G0-G1 and S phases. The results further revealed an increase in p53, p21, and p27 levels and a decrease in survivin and c-Myc protein levels. Mechanistically, ixazomib treatment resulted in the accumulation of polyubiquitinated proteins, including phosphorylated IkBa with a significant reduction of p65 subunit nuclear translocation. Altogether, our preclinical data support the rationale for in vivo testing of ixazomib in EBV-associated B-cell neoplasms. Implications: This preclinical study supports the use of oral proteasome inhibitor ixazomib for targeting NF-kB signaling in the treatment of EBV-associated B-cell neoplasms.
AB - Epstein-Barr virus (EBV) is directly implicated in several B-cell lymphoid malignancies. EBV-associated lymphomas are characterized by prominent activation of the NF-kB pathway and targeting this pathway establishes a rationale for a therapeutic approach. The ubiquitin/proteasome signaling plays an essential role in the regulation of the NF-kB pathway. Ixazomib is an FDAapproved, orally bioavailable proteasome inhibitor. Here we report the first preclinical evaluation of ixazomibmediated growth-inhibitory effects on EBV-infected B-lymphoblastoid cell lines Raji and Daudi. Ixazomib induced apoptosis in these cell lines in a dosedependent manner. Cell-cycle analysis demonstrated ixazomib treatment induced cell-cycle arrest at the G2-M phase with a concomitant decrease in G0-G1 and S phases. The results further revealed an increase in p53, p21, and p27 levels and a decrease in survivin and c-Myc protein levels. Mechanistically, ixazomib treatment resulted in the accumulation of polyubiquitinated proteins, including phosphorylated IkBa with a significant reduction of p65 subunit nuclear translocation. Altogether, our preclinical data support the rationale for in vivo testing of ixazomib in EBV-associated B-cell neoplasms. Implications: This preclinical study supports the use of oral proteasome inhibitor ixazomib for targeting NF-kB signaling in the treatment of EBV-associated B-cell neoplasms.
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U2 - 10.1158/1541-7786.MCR-18-0924
DO - 10.1158/1541-7786.MCR-18-0924
M3 - Article
C2 - 30487243
AN - SCOPUS:85064040185
VL - 17
SP - 839
EP - 844
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 4
ER -