Sinomenine sensitizes multidrug-resistant colon cancer cells (Caco-2) to doxorubicin by downregulation of MDR-1 expression

• Published in: PloS one 2014-06, Vol.9 (6), p.e98560
• Main Authors: Liu, Zhen, Duan, Zhi-Jun, Chang, Jiu-Yang, Zhang, Zhi-Feng, Chu, Rui, Li, Yu-Ling, Dai, Ke-Hang, Mo, Guang-Quan, Chang, Qing-Yong
• Format: Article
• Language: English
• Subjects: Anthracyclines; Antibiotics, Antineoplastic - pharmacology; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Binding sites; Biosynthesis; Caco-2 Cells; Cancer; Cancer cells; Cancer therapies; Celecoxib; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Chemoresistance; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Colorectal carcinoma; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Dinoprostone - metabolism; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Gastroenterology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycoproteins; Hospitals; Humans; MDR1 protein; Medicine and Health Sciences; Microbial drug resistance; Morphinans - pharmacology; Multidrug resistance; Multidrug resistant organisms; NF-kappa B - metabolism; NF-κB protein; P-Glycoprotein; Polyclonal antibodies; Proteins; Pyrazoles - pharmacology; Rodents; Sensitivity enhancement; Signal Transduction; Signaling; Studies; Substrates; Sulfonamides - pharmacology; Transcription activation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098560

Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance.