![]() ZBH-01 can be an antitumor candidate drug for preclinical study in the future.Ĭolorectal cancer (CRC) is one of the main five cancer types and the five most common causes of cancer-related deaths in China, with the incidence and mortality are continuously increasing. Additionally, CCNA2 (cyclin A2), CDK2 (cyclin-dependent kinase 2), and MYBL2 (MYB proto-oncogene like 2) might be involved in the G 0/G 1 cell cycle arrest induced by ZBH-01. The initiation of apoptosis by ZBH-01 was also superior to CPT-11/SN38, followed by the increased expression of Bax, active caspase 3, and cleaved-PARP, and decreased expression of Bcl-2. Consistently, ZBH-01 induced G 0/G 1 phase arrest in colon cancer cells, while CPT-11/SN38 caused S phase arrest. After constructing a protein–protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. ZBH-01 can induce obvious DNA damage and has superior antitumor activity against colon cancer cells compared to CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin, the in vivo active form of CPT-11) both in vivo and in vitro. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The cytotoxic activity of ZBH-01 on colon cancer cells was evaluate by MTT or Cell Counting Kit-8 (CCK8) assay, 3D and xenograft model. ![]() In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells. ![]() We previously designed a series of novel irinotecan derivatives. Irinotecan (CPT-11) is a classic chemotherapeutic agent that plays an important role in the clinical treatment of metastatic colon cancer and other malignant tumors.
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