A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle

Abstract 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. We previously designed a series of novel irinotecan derivatives and selected one representative, ZBH-01, to investigate its sophisticated antitumor mechanisms in colon tumor cells. Our current results showed that ZBH-01 has superior antitumor activity against colon cancer cells compared to CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin), both in vivo and in vitro. However, its inhibitory ability on topoisomerase I (TOP1) was weaker than these two control drugs. Moreover, 842 mRNAs were downregulated and 927 were upregulated in the ZBH-01-treated group by Next-Generation Sequencing (NGS) and bioinformatics analysis. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. Then, we constructed a protein-protein interaction (PPI) network and identified a significant cluster containing 73 genes, including 14 involved in the cell cycle process. ZBH-01 induced G0/G1 phase arrest and enhanced the levels of p53 protein in colon cancer cells, while CPT-11/SN38 caused S phase arrest. 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. Additionally, CCNA2 (cyclin A2), CDK2 (cyclin-dependent kinase 2), and MYBL2 (MYB proto-oncogene like 2) might be involved in the G0/G1 cell cycle arrest induced by ZBH-01. Overall, ZBH-01 can be an antitumor candidate drug for preclinical study in the future.