Combination of dasatinib and gemcitabine reduces the ALDH1A1 expression and the proliferation of gemcitabine-resistant pancreatic cancer MIA PaCa-2 cells.

Abstract

Gemcitabine-based chemotherapy is the standard for treatment of pancreatic cancer; however, intrinsic and acquired resistance to gemcitabine commonly occurs. Aldehyde dehydrogenase 1A1 (ALDH1A1), one of the characteristic features of tumor-initiating and/or cancer stem cell (CSC) properties, is important in both intrinsic and acquired resistance to gemcitabine. In this study, we investigated the effectiveness of dasatinib, an SRC inhibitor, and gemcitabine combination to inhibit the survivals of parental (MIA PaCa-2/P) and gemcitabine-resistant (MIA PaCa-2/GR) cell lines. In MIA PaCa-2/GR cells, the levels of phospho-SRC and ALDH1A1 were increased compared to MIA PaCa-2/P cells. Inhibition of SRC by dasatinib or siRNA synergistically enhanced gemcitabine-induced anti-proliferative effects and induced apoptotic cell death in these cells. Furthermore, combination of SRC inhibition (either by dasatinib or siRNA) and gemcitabine significantly decreased the levels of ALDH1A1 expression. These results suggest that dasatinib and gemcitabine combination may be a potential therapeutic strategy to overcome gemcitabine resistance by decreasing the levels of ALDH1A1 expression.

• Authors: Hong-Quan Duong, Yong Weon Yi, Hyo Jin Kang, Insoo Bae, Young-Joo Jang, Sahng-June Kwak, Yeon-Sun Seong
• Journal: International journal of oncology (Int J Oncol) Vol. 44 Issue 6 Pg. 2132-8 (Jun 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24676703 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyrimidines
• Thiazoles
• Deoxycytidine
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase
• ALDH1A1 protein, human
• Retinal Dehydrogenase
• Dasatinib
• Gemcitabine

Topics

• Aldehyde Dehydrogenase (genetics, metabolism)
• Aldehyde Dehydrogenase 1 Family
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dasatinib
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Pyrimidines (pharmacology)
• Retinal Dehydrogenase
• Thiazoles (pharmacology)
• Gemcitabine