Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression.

Abstract

BACKGROUND/AIM:

Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment.

MATERIALS AND METHODS:

A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression.

RESULTS:

Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 μM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4α. Combined treatment with a sub-therapeutic concentration of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells.

CONCLUSION:

Apicidin appears to be a novel anti-proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression.

• Authors: Daniel Ansari, Carlos Urey, Katarzyna Said Hilmersson, Monika P Bauden, Fredrik Ek, Roger Olsson, Roland Andersson
• Journal: Anticancer research (Anticancer Res) Vol. 34 Issue 10 Pg. 5269-76 (Oct 2014) ISSN: 1791-7530 [Electronic] Greece
• PMID: 25275019 (Publication Type: Journal Article)
• Copyright: Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Histone Deacetylase Inhibitors
• Mucin-4
• Peptides, Cyclic
• Small Molecule Libraries
• apicidin
• Deoxycytidine
• Gemcitabine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (genetics)
• Drug Screening Assays, Antitumor
• Epigenesis, Genetic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Mucin-4 (genetics)
• Pancreatic Neoplasms (drug therapy, genetics)
• Peptides, Cyclic (pharmacology)
• Small Molecule Libraries
• Gemcitabine