Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Systems Biology Center, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Oncol Rep. 2018 Jan;39(1):227-238. doi: 10.3892/or.2017.6084. Epub 2017 Nov 9.
Cepharanthine (CEP), a biscoclurine alkaloid isolated from Stephania cepharantha Hayata, 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, cyclin A 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 cyclin A 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.
石蒜裂碱（CEP）是从石蒜中分离得到的一种双稠吡咯烷生物碱，已在多种不同类型的癌细胞中显示出抗癌活性。结直肠癌（CRC）是男性和女性中最常见的癌症之一。据报道，CRC 中的突变 p53 与对包括 5-氟尿嘧啶、奥沙利铂和伊立替康在内的常用化疗药物的耐药性有关。许多研究报告称，p53 突变通过几种机制诱导化疗耐药性，包括诱导药物外排、破坏细胞周期调节、逃避细胞凋亡和上调 DNA 修复。本研究旨在评估 CEP 在 p53 突变型与 p53 野生型结直肠癌细胞中的抗癌活性，并确定其作用机制。我们的结果表明，CEP 以浓度依赖性方式诱导结直肠癌细胞死亡。值得注意的是，CEP 对 p53 突变型结直肠癌细胞系 HT-29 和 SW-620 的生长控制作用优于 p53 野生型结直肠癌细胞系 COLO-205 和 HCT-116。进一步研究其作用机制表明，CEP 可诱导 HT-29 和 COLO-205 细胞的细胞周期停滞和细胞凋亡。CEP 处理可显著增加 p53 突变型细胞系 HT-29 的 p21Waf1/Cip1 表达水平，并在较小程度上增加 p53 野生型细胞系 COLO-205 的 p21Waf1/Cip1 表达水平。此外，CEP 处理后，两种细胞系的细胞周期蛋白 A 和 Bcl-2 表达水平均显著下调。CEP 还可诱导结直肠癌细胞中 ROS 的形成。总之，我们得出结论，CEP 可有效诱导细胞周期停滞和细胞凋亡，这可能是通过上调 p21Waf1/Cip1、下调细胞周期蛋白 A 和 Bcl-2 以及诱导结直肠癌细胞中 ROS 产生来介导的。这些发现表明，CEP 可能是一种新型的抗癌药物，用于治疗对当前化疗药物耐药的 p53 突变型结直肠癌。
