Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma.

TitleDual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsMondello P, Derenzini E, Asgari Z, Philip J, Brea EJ, Seshan V, Hendrickson RC, de Stanchina E, Scheinberg DA, Younes A
JournalOncotarget
Volume8
Issue8
Pagination14017-14028
Date Published2017 Feb 21
ISSN1949-2553
KeywordsAnimals, Antineoplastic Agents, Apoptosis, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Lymphoma, B-Cell, Mass Spectrometry, Mice, Morpholines, Phosphatidylinositol 3-Kinases, Polymerase Chain Reaction, Pyrimidines, Xenograft Model Antitumor Assays
Abstract

Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with Myc and PI3K-dependent lymphomas.

DOI10.18632/oncotarget.14876
Alternate JournalOncotarget
PubMed ID28147336
PubMed Central IDPMC5355158
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P50 CA192937 / CA / NCI NIH HHS / United States
R01 CA055349 / CA / NCI NIH HHS / United States
U54 OD020355 / OD / NIH HHS / United States

Person Type: