Berberine and Evodiamine Synergically Exert Anti-colorectal Cancer Effeccts via P38/MAPK/MAPKAPK2/HSP27 Signaling Pathway
Abstract Objective: Combinatorial natural products have high application potential for treatment of complex diseases owing to their synergistic effects and multi-targeting effect. However, studies have not explored the therapeutic effect and the synergetic mechanisms of action combinations of natural products. The present study aimed sought to evaluate the synergistic antitumor effects of a combination of Berberine and Evodiamine, and explore the drug effect on proliferation, migration, invasion of HCT116 and RKO human colorectal cancer cells. Results: The effect of berberine and evodiamine at a specific paired dose (BER30μM, EVO 0.8μM) was explored. A combination of berberine and evodiamine had no effect on activity and proliferation of HCT116 and RKO cells. The combination regulates the cell cycle of HCT116 and RKO cells at different cell phases. Berberine mainly blocked the cell cycle at G0/G1 phase, whereas evodiamine induced cell cycle arrest at G2/M phase. The results showed that the combined effect of berberine and evodiamine does not offset each other, but plays a synergistic role in regulation of colon cancer cell cycle. Western blot analysis showed that the combination of berberine and evodiamine regulated cell cycle by downregulating expression of cdc25c and upregulating expression of p21. The combination significantly inhibited cell migration and invasion by regulating EMT related proteins, upregulating expression of E-cadherin and downregulating expression of N-cadherin. The combination of berberine and evodiamine significantly inhibited phosphorylation of P38 MAPK in HCT116 and RKO cells, and further inhibited phosphorylation of the downstream MAPKAPK2 and HSP27, thus playing a synergistic anti-colon cancer role.Conclusion: Berberine and Evodiamine exhibit synergistic antitumor effects by suppressing cell proliferation, inducing cell cycle arrest and inhibiting EMT by modulating P38MAPK /MAPKAPK2/HSP27 pathway.Significance of the study: To illustrate the potential mechanism of formula-based combination of natural products, and explore the potential applications of the combination and possible antitumor therapeutic targets.