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Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo.
Eur J Pharm Sci. 2018 Oct 15; 123:546-559.EJ

Abstract

At present, chemotherapy is still to be the preferred and most significant therapeutic strategy for cancer patients in clinical practice. Although Camptothecin (CPT) has been discovered for over half century, a series of CPT derivatives such as Topotecan (TPT) and irinotecan (CPT-11) have been approved and are still to be the first-line medicines for clinical application. Up to now, the topoisomerase 1 inhibitor continues to be a significant drug development research field. Based on previous study of the structure-activity relationship, we consider that the introduction of lipophilic group at C7 position can prolong the retention time and the hydroxyl esterification at C20 can eliminate the hydrogen bond interaction, stabilize the E-lactone form and promote the anti-cancer effect. In this study, we carried out an optimization at C7 and C20 positions to afford two CPT derivatives 3g and 3j. Firstly, we predicted the possibly binding sites of two compounds with topoisomerase 1 by molecular docking. Then we evaluated the anti-proliferation effect of the two novel derivatives and compared the IC50 with CPT-11. Furthermore, the induction of cell cycle arrest and apoptosis was explored through karyomorphology, flow cytometry (FCM) and Western blot analysis. At last, we evaluated the anti-cancer effect and detected the mechanism in colorectal cancer xenograft model. In brief, all the data showed that the novel CPT derivatives (3g and 3j) could inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. It suggested that the two agents may be a new potential therapeutic strategy in the future.

Authors+Show Affiliations

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.Hospital for Skin Disease, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing, China.Jiangsu Institute of Materia Medica, Nanjing Tech University, Nanjing, China.Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital of Jinan University, Zhuhai, China.Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, USA.Center of Intervention Radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital of Jinan University, Zhuhai, China. Electronic address: luligong1969@126.com.Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China. Electronic address: yuanst@cpu.edu.cn.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China. Electronic address: sunli@cpu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30118848

Citation

Du, Hongzhi, et al. "Two Novel Camptothecin Derivatives Inhibit Colorectal Cancer Proliferation Via Induction of Cell Cycle Arrest and Apoptosis in Vitro and in Vivo." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 123, 2018, pp. 546-559.
Du H, Huang Y, Hou X, et al. Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. Eur J Pharm Sci. 2018;123:546-559.
Du, H., Huang, Y., Hou, X., Quan, X., Jiang, J., Wei, X., Liu, Y., Li, H., Wang, P., Zhan, M., Ai, X., Lu, L., Yuan, S., & Sun, L. (2018). Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 123, 546-559. https://doi.org/10.1016/j.ejps.2018.08.018
Du H, et al. Two Novel Camptothecin Derivatives Inhibit Colorectal Cancer Proliferation Via Induction of Cell Cycle Arrest and Apoptosis in Vitro and in Vivo. Eur J Pharm Sci. 2018 Oct 15;123:546-559. PubMed PMID: 30118848.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. AU - Du,Hongzhi, AU - Huang,Yue, AU - Hou,Xiaoying, AU - Quan,Xingping, AU - Jiang,Jingwei, AU - Wei,Xiaohui, AU - Liu,Yang, AU - Li,Hongyang, AU - Wang,Puhai, AU - Zhan,Meixiao, AU - Ai,Xun, AU - Lu,Ligong, AU - Yuan,Shengtao, AU - Sun,Li, Y1 - 2018/08/14/ PY - 2018/04/04/received PY - 2018/07/13/revised PY - 2018/08/13/accepted PY - 2018/8/18/pubmed PY - 2019/1/15/medline PY - 2018/8/18/entrez KW - Apoptosis KW - CPT-11 (PubChem CID: 46781988) KW - Camptothecin derivatives KW - Cell cycle arrest KW - Colorectal cancer KW - Proliferation SP - 546 EP - 559 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 123 N2 - At present, chemotherapy is still to be the preferred and most significant therapeutic strategy for cancer patients in clinical practice. Although Camptothecin (CPT) has been discovered for over half century, a series of CPT derivatives such as Topotecan (TPT) and irinotecan (CPT-11) have been approved and are still to be the first-line medicines for clinical application. Up to now, the topoisomerase 1 inhibitor continues to be a significant drug development research field. Based on previous study of the structure-activity relationship, we consider that the introduction of lipophilic group at C7 position can prolong the retention time and the hydroxyl esterification at C20 can eliminate the hydrogen bond interaction, stabilize the E-lactone form and promote the anti-cancer effect. In this study, we carried out an optimization at C7 and C20 positions to afford two CPT derivatives 3g and 3j. Firstly, we predicted the possibly binding sites of two compounds with topoisomerase 1 by molecular docking. Then we evaluated the anti-proliferation effect of the two novel derivatives and compared the IC50 with CPT-11. Furthermore, the induction of cell cycle arrest and apoptosis was explored through karyomorphology, flow cytometry (FCM) and Western blot analysis. At last, we evaluated the anti-cancer effect and detected the mechanism in colorectal cancer xenograft model. In brief, all the data showed that the novel CPT derivatives (3g and 3j) could inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. It suggested that the two agents may be a new potential therapeutic strategy in the future. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/30118848/Two_novel_camptothecin_derivatives_inhibit_colorectal_cancer_proliferation_via_induction_of_cell_cycle_arrest_and_apoptosis_in_vitro_and_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(18)30383-X DB - PRIME DP - Unbound Medicine ER -