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Cell Death Dis DOI:10.1038/cddis.2013.191

Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells.

Publication TypeJournal Article
Year of Publication2013
AuthorsYuan, Y, Tang, AJ, Castoreno, AB, Kuo, S-Y, Wang, Q, Kuballa, P, Xavier, R, Shamji, AF, Schreiber, SL, Wagner, BK
JournalCell Death Dis
Volume4
Pagese690
Date Published2013 Jun 27
ISSN2041-4889
KeywordsAntineoplastic Agents, Autophagy, Benzamides, Benzimidazoles, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Drug Synergism, Gene Expression, Gossypol, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Humans, Membrane Proteins, Microtubule-Associated Proteins, Pancreatic Neoplasms, Phagosomes, Proto-Oncogene Proteins, Tumor Suppressor Protein p53
Abstract

The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells.

URLhttp://dx.doi.org/10.1038/cddis.2013.191
DOI10.1038/cddis.2013.191
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23807219?dopt=Abstract

Alternate JournalCell Death Dis
PubMed ID23807219
PubMed Central IDPMC3702302
Grant ListR37 GM038627 / GM / NIGMS NIH HHS / United States
DP2 DK083048 / DK / NIDDK NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
GM38627 / GM / NIGMS NIH HHS / United States
DK083048 / DK / NIDDK NIH HHS / United States