Open AccessA novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent
Author(s) -
Manjusha Thakar,
Yue Hu,
Michael Morreale,
Lane Lerner,
Wan Ying Lin,
Rupashree Sen,
Yi Cai,
Enusha Karunasena,
Soren Saggi,
Harold Keer,
Nita Ahuja
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0199130
Subject(s) - epigenetics , pancreatic cancer , methyltransferase , dnmt1 , cancer research , biology , azacitidine , viability assay , epigenetic therapy , dna methyltransferase , pharmacology , dna methylation , apoptosis , medicine , cancer , methylation , genetics , gene expression , gene
Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase 1 (DNMT1) and in decreasing cell viability at nanomolar concentrations. We also report that guadecitabine has increased efficacy following a delay period or as we reference, a ‘rest period’. Sensitization with guadecitabine improved response to the chemotherapeutic agent–Irinotecan- as measured by decreased cell viability and accompanied by an increase in caspase activity. Additional studies are needed to understand the mechanism of action.