COMBINATION EFFECT OF CEPHARANTHINE AND 5-FLUOROURACILON HUMAN COLON CANCER IN A MOUSE XENOGRAFT MODEL

Abstract

Cepharanthine (CEP), an alkaloid isolated from the root of Stephania cepharantha Hayata, was reported to possess anticancer activity in various cancers, including colon cancer. Recently, it has been shown to enhance anti-cancer activity of 5-fluorouracil (5-FU) against human colon cancer in vitro. The present study aimed to evaluate the effect of CEP alone and CEP in combination with 5-FU in a colon cancer xenograft model. HT-29 tumors were established in the right flank of nude mice. Then, HT-29 tumor bearing mice were treated with either 5-FU or CEP alone or 5-FU combined with CEP by intraperitoneal injection every other day for three weeks. The results showed that CEP alone or in combination with 5-FU significantly delayed tumor growth when compared with the control group. Real-time RT-PCR and western blot analysis revealed that treatment with CEP alone significantly up-regulated the expression of p21 and Bak at both mRNA and protein levels. Remarkably, the combination treatment of CEP and 5-FU increased expression of Bak and p21 mRNAs and proteins as well as reduced expression of Bcl-xl mRNA. In addition, treatment with CEP and5-FU could prevent 5-FU-induced expression of MRP1 and BCRP mRNAs. Moreover, downregulation of COX-2 mRNA was also detected in tumor tissues of animals receiving CEP alone or CEP combined with 5-FU. Taken together, it is likely that synergistic antitumor effect of 5-FU and CEP is mediated through upregulation of p21 and Bak and downregulation of COX-2 in a mouse xenograft model. Therefore, the result of this study suggest that CEP may potentially be used as a single agent or in combination with 5-FU for colon cancer treatment.