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

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Cancer chemotherapy efficacy is limited by multidrug resistance (MDR).
• MDR involves both
• pump
• and
• non-pump
• resistance mechanisms.
• Glycocholic acid (GC), a bile acid, has potential in modulating drug resistance.

Purpose of the Study:

• To investigate the effects of GC on inhibiting pump and non-pump MDR.
• To evaluate GC's ability to enhance epirubicin chemosensitivity in colon cancer cells and in vivo.
• To elucidate the molecular mechanisms underlying GC's action on MDR and apoptosis.

Main Methods:

• Experiments were conducted using human colon adenocarcinoma Caco-2 cells and rat intestine models.
• Assessed epirubicin cytotoxicity, intracellular accumulation, and absorption.
• Analyzed mRNA and promoter expression levels of key MDR and apoptosis-related genes (MDR1, MRP1, MRP2, Bcl-2, Bax, p53, caspases).

Main Results:

• GC significantly increased epirubicin's cytotoxicity and intracellular accumulation in Caco-2 cells.
• GC enhanced epirubicin absorption in rat small intestine and intensified apoptosis.
• GC and epirubicin co-treatment reduced MDR gene expression, downregulated MDR1 promoter, modulated apoptosis-related genes (Bax/Bcl-2 ratio, p53, caspases) via the mitochondrial pathway.

Conclusions:

• GC effectively inhibits both pump and non-pump MDR, significantly enhancing epirubicin's chemosensitivity.
• The combination of GC with anticancer drugs offers a promising strategy to control MDR.
• GC modulates P-gp and MRPs, and regulates apoptosis pathways, providing a novel approach for overcoming cancer drug resistance.