A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
Abstract Background 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. In this study, we select one representative, ZBH-...
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04196-2 |
| _version_ | 1797789564033564672 |
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| author | Yongqi Li Dawei Zhao Wenqiu Zhang Miaomiao Yang Zhihui Wu Weiguo Shi Shijie Lan Zhen Guo Hong Yu Di Wu |
| author_facet | Yongqi Li Dawei Zhao Wenqiu Zhang Miaomiao Yang Zhihui Wu Weiguo Shi Shijie Lan Zhen Guo Hong Yu Di Wu |
| author_sort | Yongqi Li |
| collection | DOAJ |
| description | Abstract Background 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. In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells. Methods 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. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc. Results 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. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. After constructing a protein–protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. Consistently, ZBH-01 induced G0/G1 phase arrest 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. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. |
| first_indexed | 2024-03-13T01:52:27Z |
| format | Article |
| id | doaj.art-64a12d71a4724713864111a125c61639 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-13T01:52:27Z |
| publishDate | 2023-06-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj.art-64a12d71a4724713864111a125c616392023-07-02T11:25:40ZengBMCJournal of Translational Medicine1479-58762023-06-0121111710.1186/s12967-023-04196-2A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycleYongqi Li0Dawei Zhao1Wenqiu Zhang2Miaomiao Yang3Zhihui Wu4Weiguo Shi5Shijie Lan6Zhen Guo7Hong Yu8Di Wu9Department of Cancer Centre, The First Hospital of Jilin UniversityDepartment of Breast Tumor, Jilin Cancer HospitalDepartment of Cancer Centre, The First Hospital of Jilin UniversityInstitute of Translational Medicine, The First Hospital of Jilin UniversityInstitute of Translational Medicine, The First Hospital of Jilin UniversityInstitute of Pharmacology and Toxicology Academy of Military Medical SciencesDepartment of Cancer Centre, The First Hospital of Jilin UniversityDepartment of Cancer Centre, The First Hospital of Jilin UniversityCell Biology Laboratory, Jilin Province Institute of Cancer Prevention and Treatment, Jilin Cancer HospitalDepartment of Cancer Centre, The First Hospital of Jilin UniversityAbstract Background 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. In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells. Methods 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. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc. Results 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. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. After constructing a protein–protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. Consistently, ZBH-01 induced G0/G1 phase arrest 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. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future.https://doi.org/10.1186/s12967-023-04196-2Irinotecan derivative ZBH-01Colorectal cancerNext-generation sequencingDifferentially expressed genesCell cycleApoptosis |
| spellingShingle | Yongqi Li Dawei Zhao Wenqiu Zhang Miaomiao Yang Zhihui Wu Weiguo Shi Shijie Lan Zhen Guo Hong Yu Di Wu A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle Journal of Translational Medicine Irinotecan derivative ZBH-01 Colorectal cancer Next-generation sequencing Differentially expressed genes Cell cycle Apoptosis |
| title | A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| title_full | A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| title_fullStr | A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| title_full_unstemmed | A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| title_short | A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| title_sort | novel camptothecin derivative zbh 01 exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle |
| topic | Irinotecan derivative ZBH-01 Colorectal cancer Next-generation sequencing Differentially expressed genes Cell cycle Apoptosis |
| url | https://doi.org/10.1186/s12967-023-04196-2 |
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