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  2. Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin

Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin

  • Eur J Pharm Sci. 2008 Sep 2;35(1-2):52-67. doi: 10.1016/j.ejps.2008.06.003.
Y L Lo 1 C T Ho F L Tsai
Affiliations

Affiliation

  • 1 Department of Biological Sciences and Technology, National University of Tainan, Tainan City 700, Taiwan. yulilo@mail.nutn.edu.tw
Abstract

Cancer-cell resistance to chemotherapy limits the efficacy of Cancer treatment. The primary mechanisms of multidrug resistance (MDR) are "pump" and "non-pump" resistance. We evaluated the effects and mechanisms of glycocholic acid (GC), a bile acid, on inhibiting pump and non-pump resistance, and increasing the chemosensitivity of epirubicin in human colon adenocarcinoma Caco-2 cells and rat intestine. GC increased the cytotoxicity of epirubicin, significantly increased the intracellular accumulation of epirubicin in Caco-2 cells and the absorption of epirubicin in rat small intestine, and intensified epirubicin-induced Apoptosis. GC and epirubicin significantly reduced mRNA expression levels of human intestinal MDR1, MDR-associated protein (MRP)1, and MRP2; downregulated the MDR1 promoter region; suppressed the mRNA expression of Bcl-2; induced the mRNA expression of Bax; and significantly increased the Bax-to-Bcl-2 ratio and the mRNA levels of p53, caspase-9 and -3. This suggests that GC- and epirubicin-induced Apoptosis was mediated through the mitochondrial pathway. We conclude that simultaneous suppression of pump and non-pump resistance dramatically increased the chemosensitivity of epirubicin. A combination of Anticancer drugs with GC can control MDR via a mechanism that involves modulating P-gp and MRPs as well as regulating apoptosis-related pathways.

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