Indomethacin and SC236 enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells via inhibiting P-glycoprotein and MRP1 expression.

Abstract

Doxorubicin is a chemotherapeutic drug widely used for the treatment of hepatocellular carcinoma but its efficacy is restricted by multidrug resistance. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2-selective inhibitors exhibit anti-cancer properties as well as abilities to overcome drug resistance. In the present study, indomethacin (a NSAID) and SC236 (a COX-2-selective inhibitor) enhanced the cytotoxicity of doxorubicin in the hepatocellular carcinoma cell line HepG2 and its drug-resistant sub-line R-HepG2. Both drugs increased the intracellular accumulation and retention of doxorubicin in vitro. The effects were not reversed by prostaglandin E(2), implicating a COX-independent mechanism. Indomethacin and SC236 partially reversed the increase in expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) induced by doxorubicin in R-HepG2 cells. In conclusion, indomethacin and SC236 increased the intracellular accumulation and retention of doxorubicin and thus its cytotoxicity in HepG2 and drug-resistant HepG2 cells. These effects, mediated through decrease in P-gp and MRP1 expression and/or direct inhibition of P-gp activity, may improve multidrug resistant-cancer chemotherapy.

• Authors: Cai-Guo Ye, William Ka-Kei Wu, John Hok-Keung Yeung, Hai-Tao Li, Zhi-Jie Li, Clover Ching-Man Wong, Shun-Xiang Ren, Lin Zhang, Kwok-Pui Fung, Chi-Hin Cho
• Journal: Cancer letters (Cancer Lett) Vol. 304 Issue 2 Pg. 90-6 (May 28 2011) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 21377266 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• Cyclooxygenase 2 Inhibitors
• Multidrug Resistance-Associated Proteins
• Pyrazoles
• Sulfonamides
• Doxorubicin
• Indomethacin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, drug effects)
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Cell Separation
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Flow Cytometry
• Humans
• Indomethacin (pharmacology)
• Liver Neoplasms (metabolism)
• Microscopy, Confocal
• Multidrug Resistance-Associated Proteins (biosynthesis, drug effects)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)