Xu Zhenyu, Jiang Hui, Zhu Yanhong, Wang Huifang, Jiang Jia, Chen Lu, Xu Wenke, Hu Tao, Cho Chi Hin
Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China.
Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China.
Chem Biol Interact. 2017 Aug 1;273:48-55. doi: 10.1016/j.cbi.2017.06.003. Epub 2017 Jun 9.
The development of novel chemotherapeutic agents is highly desired for colon cancer treatment, in particular for the multidrug-resistant cancer types. Cryptotanshinone (CTS), an active quinoid diterpene isolated from Salvia miltiorrhiza Bunge, was previously reported to induce autophagy in various colon cancer cell lines. However, its mechanisms of action have not been fully understood. The current study aims to explore the mechanisms by which CTS induces autophagy in a multidrug-resistant human colon cancer cell line SW620 Ad300. Using MTT assay, CTS at 10 μM exhibited no significant cytotoxicity on human normal colon fibroblasts CCD-18Co, but induced 45.67% and 48.35% cell death in SW620 and SW620 Ad300 cells, respectively. Further studies revealed that CTS induced weak apoptosis (9.37%) and significant caspase-independent cell death in SW620 Ad300 cells. In the same cell line, CTS also induced significant autophagy, which was found to promote cell death and to mediate the cytotoxicity of CTS in these multidrug-resistant cells. Moreover, activation of ROS-p38 MAPK-NF-κB signaling pathway was involved in autophagic cell death induced by CTS in SW620 Ad300 cells. Interestingly, our results also demonstrated a complementary relationship between CTS-induced apoptosis and autophagic cell death in SW620 Ad300 cells. Taken together, CTS induces autophagic cell death in SW620 Ad300 cells via the ROS-p38 MAPK-NF-κB signaling pathway, and it might be a potential candidate as a chemotherapeutic agent for the treatment of multidrug-resistant colon cancer.
新型化疗药物的研发对于结肠癌治疗，尤其是对多药耐药癌症类型的治疗来说是非常必要的。隐丹参酮（CTS）是从丹参中分离出的一种活性醌类二萜，此前有报道称其可在多种结肠癌细胞系中诱导自噬。然而，其作用机制尚未完全明确。本研究旨在探究CTS在多药耐药人结肠癌细胞系SW620 Ad300中诱导自噬的机制。通过MTT法检测发现，10 μM的CTS对人正常结肠成纤维细胞CCD - 18Co无明显细胞毒性，但分别诱导SW620和SW620 Ad300细胞发生45.67%和48.35%的细胞死亡。进一步研究表明，CTS在SW620 Ad300细胞中诱导了较弱的凋亡（9.37%）和显著的非半胱天冬酶依赖性细胞死亡。在同一细胞系中，CTS还诱导了显著的自噬，发现其可促进细胞死亡并介导CTS在这些多药耐药细胞中的细胞毒性。此外，ROS - p38 MAPK - NF - κB信号通路的激活参与了CTS在SW620 Ad300细胞中诱导的自噬性细胞死亡。有趣的是，我们的结果还表明CTS诱导的凋亡与SW620 Ad300细胞中的自噬性细胞死亡之间存在互补关系。综上所述，CTS通过ROS - p38 MAPK - NF - κB信号通路在SW620 Ad300细胞中诱导自噬性细胞死亡，它可能是治疗多药耐药结肠癌的一种潜在化疗药物候选物。
