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Abstract
Dihydroartemisinin (DHA), a well-known antimalarial drug, has been widely investigated for its antitumor effects in multiple malignancies. However, its effects and regulatory mechanisms in colorectal cancer (CRC) are still unproved. In this study, in vitro experiments including CCK8, EdU, Transwell, and flow cytometry analyses and an in vivo tumorigenesis model were conducted to assess the effects of DHA on the bio-behaviors of CRC cells. Additionally, RNA-seq combined with gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses was used to obtain the targets of DHA, and these were verified by molecular docking, qRT-PCR, and Western blotting. As a result, we found that DHA significantly suppressed the proliferation, DNA synthesis, and invasive capabilities and induced cell apoptosis and cell cycle arrest in HCT116, DLD1, and RKO cells in vitro and in vivo. Further analyses indicated that the targets of DHA were predominantly enriched in cell cycle-associated pathways, including CDK1, CCNB1, and PLK1; and DHA could bind with the CDK1/CCNB1 complex and inhibit the activation of CDK1/CCNB1/PLK1 signaling. Moreover, cucurbitacin E, a specific inhibitor of the CDK1/CCNB1 axis, enhanced the inhibitory effects of DHA on DNA synthesis and colony formation in HCT116 and DLD1 cells. In short, DHA could suppress the tumorigenesis and cycle progression of CRC cells by targeting CDK1/CCNB1/PLK1 signaling.
Highlights
Colorectal cancer (CRC), one of the most malignant tumors, accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths [1]
We found that DHA significantly inhibited the proliferation viability of HCT116, DLD1, and RKO cells in a time- and dose-dependent manner as compared with the control group (Figures 1B–D)
Colony formation and EdU assays showed that DHA remarkably suppressed cell colony formation (Figures 1E, F) and DNA synthesis (Figures 1G, H) in HCT116, DLD1, and RKO cells
Summary
Colorectal cancer (CRC), one of the most malignant tumors, accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths [1]. Because of the absence of the specific and Dihydroartemisinin Suppresses Colorectal Cancer distinct symptoms, most patients are diagnosed at an advanced and unresectable stage, and their prognosis is not optimistic. DHA can ameliorate psoriatic skin inflammation by diminishing CD8+ T-cell memory [10], modulate the mammalian target of rapamycin pathway [11], and suppress lipopolysaccharide-induced acute kidney injury by inhibiting inflammation and oxidative stress [12]. Numerous studies reveal that DHA can exhibit antitumor effects in a variety of tumors, such as epithelial ovarian cancer [15], lung cancer [16], bladder cancer [17], breast cancer [18], and CRC [19]
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