Cepharanthine exhibits a potent anticancer activity in p53-mutated colorectal cancer cells through upregulation of p21Waf1/Cip1.

Abstract

Cepharanthine(CEP), a biscoclurine alkaloid isolated from StephaniacepharanthaHayata, has demonstrated anticancer activity in several different types of cancer cells. Colorectal cancer(CRC) is one of the most common cancers in both men and women. Mutated p53 in CRC was reported to be associated with resistance to commonly used chemotherapeutic agents including, 5‑fluorouracil, oxaliplatin and irinotecan. Many studies reported that mutation of p53 induced chemoresistance through several mechanisms, including induction of drug efflux, disruption of cell cycle regulation, evasion of apoptosis and upregulation of DNA repair. This study aimed to evaluate the anticancer activity of CEP in p53 mutant versus p53 wild-type colorectal cancer cells and determine its underlying mechanisms of action. Our results showed that CEP induced colorectal cancer cell death in a concentration-dependent manner. Remarkably, CEP was more effective in controlling the growth of the p53 mutant colorectal cancer cell lines, HT‑29 and SW-620, than the p53 wild-type colorectal cancer cell lines, COLO‑205 and HCT-116. Further studies on the underlying mechanisms revealed that CEP could induce cell cycle arrest and apoptosis in both HT‑29 and COLO‑205 cells. Treatment with CEP dramatically increased p21Waf1/Cip1 expression levels of the p53 mutant cell line HT‑29 and to a lesser extent, the p53 wild-type cell line COLO‑205. In addition, cyclinA and Bcl‑2 expression levels of both cell lines were significantly downregulated following treatment with CEP. CEP also induced ROS formation in colorectal cancer cells. Taken together, we concluded that CEP effectively induced cell cycle arrest and apoptosis which may be mediated through upregulation of p21Waf1/Cip1, downregulation of cyclinA and Bcl‑2 and induction of ROS production in colorectal cancer cells. These findings suggested that CEP could potentially be a novel anticancer agent for p53 mutant colorectal cancer cells which are often resistant to current chemotherapeutic agents.