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A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage.
Anticancer Agents Med Chem. 2019; 19(3):365-374.AA

Abstract

OBJECTIVE

The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms.

BACKGROUND

Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression.

METHODS

Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage.

RESULTS

Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells.

CONCLUSION

Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

Authors+Show Affiliations

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.Department of Gynaecology and Obstetrics, Southeast University Affiliated Zhongda Hospital, Nanjing, Jiangsu, China.Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Provincial Institue of Materia Medica, Nanjing Technology University, Nanjing, Jiangsu, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, China.Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30523769

Citation

Liu, Yang, et al. "A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage." Anti-cancer Agents in Medicinal Chemistry, vol. 19, no. 3, 2019, pp. 365-374.
Liu Y, Zhang J, Feng S, et al. A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage. Anticancer Agents Med Chem. 2019;19(3):365-374.
Liu, Y., Zhang, J., Feng, S., Zhao, T., Li, Z., Wang, L., Wang, P., Du, H., Yuan, S., & Sun, L. (2019). A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage. Anti-cancer Agents in Medicinal Chemistry, 19(3), 365-374. https://doi.org/10.2174/1871520619666181207102037
Liu Y, et al. A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage. Anticancer Agents Med Chem. 2019;19(3):365-374. PubMed PMID: 30523769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage. AU - Liu,Yang, AU - Zhang,Jingyin, AU - Feng,Shuyun, AU - Zhao,Tingli, AU - Li,Zhengzheng, AU - Wang,Lai, AU - Wang,Puhai, AU - Du,Hongzhi, AU - Yuan,Shengtao, AU - Sun,Li, PY - 2018/03/07/received PY - 2018/11/14/revised PY - 2018/11/20/accepted PY - 2018/12/14/pubmed PY - 2019/12/27/medline PY - 2018/12/8/entrez KW - Camptothecin derivative 3j KW - DNA damage KW - cell cycle arrest KW - non-small cell lung cancer KW - proliferation KW - topo I. SP - 365 EP - 374 JF - Anti-cancer agents in medicinal chemistry JO - Anticancer Agents Med Chem VL - 19 IS - 3 N2 - OBJECTIVE: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. BACKGROUND: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. METHODS: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. RESULTS: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. CONCLUSION: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies. SN - 1875-5992 UR - https://www.unboundmedicine.com/medline/citation/30523769/A_Novel_Camptothecin_Derivative_3j_Inhibits_Nsclc_Proliferation_Via_Induction_of_Cell_Cycle_Arrest_By_Topo_I_Mediated_DNA_Damage_ L2 - http://www.eurekaselect.com/168147/article DB - PRIME DP - Unbound Medicine ER -