Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua, has been shown to exhibit antitumor activity in various cancer cells, including colorectal cancer. However, the detailed mechanisms underlying its antitumor activity in colorectal cancer remain to be elucidated. In the present study, we investigated DHA-induced apoptosis in human colorectal cancer HCT-116 cells in vitro. The results showed that DHA treatment significantly reduced cell viability in a concentration- and time-dependent manner. Furthermore, DHA induced G1 cell cycle arrest, apoptotic cell death, and accumulation of reactive oxygen species (ROS). We also found that DHA decreased the mitochondrial membrane potential; activated the caspase-3, caspase-8, and caspase-9; and increased the ratio of Bax/Bcl-2. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria were observed. Strikingly, the free radical scavenger N-acetylcysteine or the caspase-3 inhibitor Ac-DEVD-CHO significantly prevented DHA-induced apoptotic cell death. Taken together, we concluded that DHA-triggered apoptosis in HCT-116 cells occurs through the ROS-mediated mitochondria-dependent pathway. Our data suggest that DHA has great potential to be developed as a novel therapeutic agent for the treatment of human colorectal cancer.

Dihydroartemisinin (DHA) is a promising anti-cancer compound capable of inhibiting proliferation and inducing apoptosis of various cancer cells, including colorectal cancer. However, the molecular mechanisms have not been well understood. This study aimed to explore the underlying mechanism of DHA-induced apoptosis in HCT-116 cells. Cell counting kit-8 assay and flow cytometry analysis confirmed that DHA inhibited proliferation, arrested cell cycle at G0/G1 phase, and enhanced apoptosis in HCT-116 cells. Fluo-3/AM-stained flow cytometry assay revealed that the intracellular Ca(2+) concentration of HCT-116 cells was increased significantly after DHA treatment. Meanwhile, the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA) was appeared to be reduced in a dose-dependent manner. We further detected the upregulated expression of CAAT/enhancer binding protein homologous protein (CHOP) in DHA-treated HCT-116 cells. Conversely, silencing CHOP resulted in a decrease of DHA-induced apoptosis. In addition, the expression of Bax in cytoplasm was elevated significantly along with the sharply decline of Bcl-2 expression in DHA-treated HCT-116 cells. Moreover, the distributions of Bid on mitochondria were increased, accompanied by the activation of caspase-3 in the presence of DHA. Overall, our data indicated that DHA triggered endoplasmic reticulum (ER) stress through inhibiting SERCA activity to release intracellular Ca(2+) from ER, the upregulated expression of CHOP activated mitochondrial apoptosis pathway to induce apoptosis of HCT-116 cells. Therefore, our findings provide a theoretical foundation for DHA as a potential candidate in treatment of colorectal cancer.

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OR = 1.23, 95%CI 1.03-1.46, P = 0.020). Subgroup analysis based on ethnicity showed that there was an obvious association between hOGG1 C8069G polymorphism and increased risk of colorectal cancer in the Caucasian population but not in the Asian population. The findings from the meta-analysis suggest that there is an obvious association between hOGG1 C8069G polymorphism and increased risk of colorectal cancer, especially in the Caucasian population.

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