Dihydroartemisinin potentiates antitumor activity of 5-fluorouracil against a resistant colorectal cancer cell line

Although the combination of chemotherapy and surgical resection has effectively increased the survival rate of colorectal Cancer patients in recent decades, acquired drug resistance is still a problem that leads to treatment failure. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently been reported to show Anticancer effects against numerous types of Cancer, including colorectal Cancer. This study showed that DHA exerted a strong Anticancer effect against several colorectal Cancer cell lines. We also found that p53 knockout colorectal Cancer HCT116 cells (HCT116 TP53^-/-) were not sensitive to 5-fluorouracil (5-FU) treatment, unlike wild-type HCT116 cells. Interestingly, co-treatment with DHA could effectively restore the Anticancer effect of 5-FU against HCT116 TP53^-/- cells, which manifested as the inhibition of proliferation and induction of Reactive Oxygen Species (ROS)-mediated Apoptosis and was accompanied by the upregulation of B-cell lymphoma 2 (Bcl-2) and downregulation of the BCL-2-associated X protein (Bax). These findings suggested that DHA could effectively sensitize cells to 5-FU through ROS-mediated Apoptosis and the alteration of the Bcl-2/Bax expression ratio, which indicated that this may be one of the mechanisms of the DHA-promoted 5-FU Anticancer effect.