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

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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Li, Yongqi [verfasserIn] Zhao, Dawei Zhang, Wenqiu Yang, Miaomiao Wu, Zhihui Shi, Weiguo Lan, Shijie Guo, Zhen Yu, Hong Wu, Di

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Irinotecan derivative ZBH-01 Colorectal cancer Next-generation sequencing Differentially expressed genes Cell cycle Apoptosis

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 21(2023), 1 vom: 29. Juni
Übergeordnetes Werk:	volume:21 ; year:2023 ; number:1 ; day:29 ; month:06

Links:	Volltext

DOI / URN:	10.1186/s12967-023-04196-2

Katalog-ID:	SPR052098338

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245	1	2	\|a A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
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520			\|a 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future.
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allfields	10.1186/s12967-023-04196-2 doi (DE-627)SPR052098338 (SPR)s12967-023-04196-2-e DE-627 ger DE-627 rakwb eng Li, Yongqi verfasserin aut A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zhao, Dawei aut Zhang, Wenqiu aut Yang, Miaomiao aut Wu, Zhihui aut Shi, Weiguo aut Lan, Shijie aut Guo, Zhen aut Yu, Hong aut Wu, Di (orcid)0000-0002-0742-0556 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 21(2023), 1 vom: 29. Juni (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:21 year:2023 number:1 day:29 month:06 https://dx.doi.org/10.1186/s12967-023-04196-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2023 1 29 06
spelling	10.1186/s12967-023-04196-2 doi (DE-627)SPR052098338 (SPR)s12967-023-04196-2-e DE-627 ger DE-627 rakwb eng Li, Yongqi verfasserin aut A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zhao, Dawei aut Zhang, Wenqiu aut Yang, Miaomiao aut Wu, Zhihui aut Shi, Weiguo aut Lan, Shijie aut Guo, Zhen aut Yu, Hong aut Wu, Di (orcid)0000-0002-0742-0556 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 21(2023), 1 vom: 29. Juni (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:21 year:2023 number:1 day:29 month:06 https://dx.doi.org/10.1186/s12967-023-04196-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2023 1 29 06
allfields_unstemmed	10.1186/s12967-023-04196-2 doi (DE-627)SPR052098338 (SPR)s12967-023-04196-2-e DE-627 ger DE-627 rakwb eng Li, Yongqi verfasserin aut A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zhao, Dawei aut Zhang, Wenqiu aut Yang, Miaomiao aut Wu, Zhihui aut Shi, Weiguo aut Lan, Shijie aut Guo, Zhen aut Yu, Hong aut Wu, Di (orcid)0000-0002-0742-0556 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 21(2023), 1 vom: 29. Juni (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:21 year:2023 number:1 day:29 month:06 https://dx.doi.org/10.1186/s12967-023-04196-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2023 1 29 06
allfieldsGer	10.1186/s12967-023-04196-2 doi (DE-627)SPR052098338 (SPR)s12967-023-04196-2-e DE-627 ger DE-627 rakwb eng Li, Yongqi verfasserin aut A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zhao, Dawei aut Zhang, Wenqiu aut Yang, Miaomiao aut Wu, Zhihui aut Shi, Weiguo aut Lan, Shijie aut Guo, Zhen aut Yu, Hong aut Wu, Di (orcid)0000-0002-0742-0556 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 21(2023), 1 vom: 29. Juni (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:21 year:2023 number:1 day:29 month:06 https://dx.doi.org/10.1186/s12967-023-04196-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2023 1 29 06
allfieldsSound	10.1186/s12967-023-04196-2 doi (DE-627)SPR052098338 (SPR)s12967-023-04196-2-e DE-627 ger DE-627 rakwb eng Li, Yongqi verfasserin aut A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zhao, Dawei aut Zhang, Wenqiu aut Yang, Miaomiao aut Wu, Zhihui aut Shi, Weiguo aut Lan, Shijie aut Guo, Zhen aut Yu, Hong aut Wu, Di (orcid)0000-0002-0742-0556 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 21(2023), 1 vom: 29. Juni (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:21 year:2023 number:1 day:29 month:06 https://dx.doi.org/10.1186/s12967-023-04196-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2023 1 29 06
language	English
source	Enthalten in Journal of translational medicine 21(2023), 1 vom: 29. Juni volume:21 year:2023 number:1 day:29 month:06
sourceStr	Enthalten in Journal of translational medicine 21(2023), 1 vom: 29. Juni volume:21 year:2023 number:1 day:29 month:06
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Irinotecan derivative ZBH-01 Colorectal cancer Next-generation sequencing Differentially expressed genes Cell cycle Apoptosis
isfreeaccess_bool	true
container_title	Journal of translational medicine
authorswithroles_txt_mv	Li, Yongqi @@aut@@ Zhao, Dawei @@aut@@ Zhang, Wenqiu @@aut@@ Yang, Miaomiao @@aut@@ Wu, Zhihui @@aut@@ Shi, Weiguo @@aut@@ Lan, Shijie @@aut@@ Guo, Zhen @@aut@@ Yu, Hong @@aut@@ Wu, Di @@aut@@
publishDateDaySort_date	2023-06-29T00:00:00Z
hierarchy_top_id	369084136
id	SPR052098338
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR052098338</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230630064744.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230630s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s12967-023-04196-2</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR052098338</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s12967-023-04196-2-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Li, Yongqi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2023</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Irinotecan derivative ZBH-01</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Colorectal cancer</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Next-generation sequencing</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Differentially expressed genes</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cell cycle</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Apoptosis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhao, Dawei</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhang, Wenqiu</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yang, Miaomiao</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wu, Zhihui</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Shi, Weiguo</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lan, Shijie</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Guo, Zhen</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yu, Hong</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wu, Di</subfield><subfield code="0">(orcid)0000-0002-0742-0556</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Journal of translational medicine</subfield><subfield code="d">London : BioMed Central, 2003</subfield><subfield code="g">21(2023), 1 vom: 29. 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author	Li, Yongqi
spellingShingle	Li, Yongqi misc Irinotecan derivative ZBH-01 misc Colorectal cancer misc Next-generation sequencing misc Differentially expressed genes misc Cell cycle misc Apoptosis A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
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topic_title	A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle Irinotecan derivative ZBH-01 (dpeaa)DE-He213 Colorectal cancer (dpeaa)DE-He213 Next-generation sequencing (dpeaa)DE-He213 Differentially expressed genes (dpeaa)DE-He213 Cell cycle (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213
topic	misc Irinotecan derivative ZBH-01 misc Colorectal cancer misc Next-generation sequencing misc Differentially expressed genes misc Cell cycle misc Apoptosis
topic_unstemmed	misc Irinotecan derivative ZBH-01 misc Colorectal cancer misc Next-generation sequencing misc Differentially expressed genes misc Cell cycle misc Apoptosis
topic_browse	misc Irinotecan derivative ZBH-01 misc Colorectal cancer misc Next-generation sequencing misc Differentially expressed genes misc Cell cycle misc Apoptosis
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title	A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
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title_full	A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
author_sort	Li, Yongqi
journal	Journal of translational medicine
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author_browse	Li, Yongqi Zhao, Dawei Zhang, Wenqiu Yang, Miaomiao Wu, Zhihui Shi, Weiguo Lan, Shijie Guo, Zhen Yu, Hong Wu, Di
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author-letter	Li, Yongqi
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title_sort	novel camptothecin derivative, zbh-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
title_auth	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-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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. © The Author(s) 2023
abstractGer	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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. © The Author(s) 2023
abstract_unstemmed	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 $ G_{0} $/$ G_{1} $ 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 $ G_{0} $/$ G_{1} $ cell cycle arrest induced by ZBH-01. Conclusions ZBH-01 can be an antitumor candidate drug for preclinical study in the future. © The Author(s) 2023
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container_issue	1
title_short	A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle
url	https://dx.doi.org/10.1186/s12967-023-04196-2
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author2	Zhao, Dawei Zhang, Wenqiu Yang, Miaomiao Wu, Zhihui Shi, Weiguo Lan, Shijie Guo, Zhen Yu, Hong Wu, Di
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A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle

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