Open AccessSmall molecule growth inhibitors of human oncogenic gammaherpesvirus infected B‐cells
Author(s) -
Dzeng Richard K.,
Jha Hem Chandra,
Lu Jie,
Saha Abhik,
Banerjee Sagarika,
Robertson Erle S.
Publication year - 2015
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2014.09.006
Subject(s) - biology , epstein–barr virus , small molecule , cell growth , growth inhibition , cancer research , cell culture , virus , virology , gene knockdown , genetics
Epstein–Barr virus (EBV) and Kaposi's sarcoma‐associated herpesvirus (KSHV) are two human gammaherpesviruses associated with a broad spectrum of B‐cell lymphomas, most acutely in immuno‐compromised populations. However, there are no drugs which specifically target KSHV or EBV‐associated lymphomas. To identify small molecules which selectively inhibit the growth of EBV or KSHV‐associated B‐cell lines, we performed a fluorescence based high‐throughput screen on multiple stable GFP expressing virus‐infected or uninfected B‐cell lines. We identified 40 initial compounds with selective growth inhibition and subsequently determined the 50% growth inhibitory concentrations (GI50) for each drug. We further examined compounds with higher specificity to explore the underlying molecular mechanisms using transcription factor analysis, as well as a shRNA based knockdown strategy. Our data identified ten compounds with relatively high efficacy for growth inhibition. Two novel small molecules, NSC#10010 and NSC#65381 were potent growth inhibitors for gammaherpesvirus‐associated B‐lymphomas through activation of both the NF‐κB and c‐Myc‐mediated signaling pathways. These drugs can serve as potential lead compounds to expand the current therapeutic window against EBV or KSHV‐associated human B‐cell malignancies.