Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

Author(s): Yang Liu, Jingyin Zhang, Shuyun Feng, Tingli Zhao, Zhengzheng Li, Lai Wang, Puhai Wang, Hongzhi Du*, Shengtao Yuan* and Li Sun*

Volume 19, Issue 3, 2019

Page: [365 - 374] Pages: 10

DOI: 10.2174/1871520619666181207102037

Price: $65

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.

Keywords: Camptothecin derivative 3j, non-small cell lung cancer, proliferation, cell cycle arrest, topo I, DNA damage.

« Previous Next »
Graphical Abstract

[1]
Ali, I. UD-Din, R.; Saleem, K.; Enein, H.Y.; Rather, A. Social aspects of cancer genesis. Can Ther., 2011, 8, 6-14.
[2]
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M. Heterocyclic scaffolds: Centrality in anticancer drug development. Curr. Drug Targets, 2015, 16(7), 711-734.
[3]
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Alwarthan, A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings: DNA binding, molecular docking, and anticancer studies. J. Mol. Liq., 2017, 234, 391-402.
[4]
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Glutamic acid and its derivatives: Candidates for rational design of anticancer drugs. Fut Med. Chem., 2013, 5(8), 961-978.
[5]
Ali, I.; Wani, W.A.; Saleem, K.; Wesselinova, D. Syntheses, DNA binding and anticancer profiles of L-glutamic acid ligand and its copper(II) and ruthenium(III) complexes. Med. Chem. Res., 2013, 22, 1386-1398.
[6]
Ali, I.; Wani, W.A.; Saleem, K.; Hsieh, M.F. Anticancer metallodrugs of glutamic acid sulphonamides: In silico, DNA binding, hemolysis and anticancer studies. RSC Adv, 2014, 4(56), 29629-29641.
[7]
Ali, I.; Haque, A.; Saleem, K.; Hsieh, M.F. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: Synthesis, pharmacological and simulation studies. Bioorg. Med. Chem., 2013, 21(13), 3808-3820.
[8]
Ali, I.; Saleem, K.; Wesselinova, D.; Haque, A. Synthesis, DNA binding, hemolytic, and anti-cancer assays of curcumin I-based ligands and their ruthenium(III) complexes. Med. Chem. Res., 2013, 22(3), 1386-1398.
[9]
Ali, I.; Wani, W.A.; Saleem, K.; Haque, A. Platinum compounds: A hope for future cancer chemotherapy. Anticanc. Agents Med. Chem., 2013, 13(2), 296-306.
[10]
Haque, A.; Saleem, K.; Wani, W.A.; Ali, I. Thalidomide: A banned drug resurged into future anticancer drug. Curr. Drug Ther., 2012, 7, 13-23.
[11]
Ali, I.; Wani, W.A.; Saleem, K.; Hsieh, M.F. Design and synthesis of thalidomide based dithiocarbamate Cu(II), Ni(II) and Ru(III) complexes as anticancer agents. Polyhedron, 2013, 56, 134-143.
[12]
Saleem, K.; Wani, W.A.; Haque, A.; Milhotra, A.; Ali, I. Nanodrugs: Magic bullets in cancer chemotherapy. Topics Anti Canc. Res., 2013, 58(2), 437-494.
[13]
Ali, I.; Lone, M.N.; Suhail, M.; Mukhtar, S.D. Advances in nanocarriers for anticancer drugs delivery. Curr. Med. Chem., 2016, 23, 2159-2187.
[14]
Ali, I. Nano anti-cancer drugs: Pros and cons and future perspectives. Curr. Canc Drug Targets, 2011, 11(2), 131-134.
[15]
Ali, I. Natural products: Human friendly anti-cancer medications. Egyp. Pharm. J., 2010, 9, 133-179.
[16]
Kentepozidis, N.; Economopoulou, P.; Christofyllakis, C.; Chelis, L.; Polyzos, A.; Vardakis, N.; Koinis, F.; Vamvakas, L.; Katsaounis, P.; Kalbakis, K.; Nikolaou, C.; Georgoulias, V.; Kotsakis, A. Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG). Clin. Transl. Oncol., 2017, 19(3), 317-325.
[17]
Karthaus, M.; Ballo, H.; Abenhardt, W.; Steinmetz, T.; Geer, T.; Schimke, J.; Braumann, D.; Behrens, R.; Behringer, D.; Kindler, M.; Messmann, H.; Boeck, H.P.; Greinwald, R.; Kleeberg, U. Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer. Oncology, 2005, 68(4-6), 326-332.
[18]
Verbiest, V.; Montaudon, D.; Tautu, M.T.; Moukarzel, J.; Portail, J.P.; Markovits, J.; Robert, J.; Ichas, F.; Pourquier, P. Protein arginine (N)-methyl transferase 7 (PRMT7) as a potential target for the sensitization of tumor cells to camptothecins. FEBS Lett., 2008, 582(10), 1483-1489.
[19]
Mattern, M.R.; Mong, S.M.; Bartus, H.F.; Mirabelli, C.K.; Crooke, S.T.; Johnson, R.K. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Canc Res., 1987, 47(7), 1793-1798.
[20]
Mazzini, S.; Bellucci, M.C.; Dallavalle, S.; Fraternali, F.; Mondelli, R. Mode of binding of camptothecins to double helix oligonucleotides. Org. Biomol. Chem., 2004, 2(4), 505-513.
[21]
Yanai, M.; Makino, H.; Ping, B.; Takeda, K.; Tanaka, N.; Sakamoto, T.; Yamaguchi, K.; Kodani, M.; Yamasaki, A.; Igishi, T.; Shimizu, E. DNA-PK inhibition by NU7441 enhances chemosensitivity to topoisomerase inhibitor in non-small cell lung carcinoma cells by blocking DNA damage repair. Yonago Acta Med., 2017, 60(1), 9-15.
[22]
Samori, C.; Guerrini, A.; Varchi, G.; Fontana, G.; Bombardelli, E.; Tinelli, S.; Beretta, G.L.; Basili, S.; Moro, S.; Zunino, F.; Battaglia, A. Semisynthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins. J. Med. Chem., 2009, 52(4), 1029-1039.
[23]
Xu, C.; Barchet, T.M.; Mager, D.E. Quantitative structure-property relationships of camptothecins in humans. Canc Chemother. Pharmacol., 2010, 65(2), 325-333.
[24]
Peng, G.; Lei, Z.; Jiale, W.; Puhai, W.; Li, S.; Shengtao, Y. The synthesis and antitumor activity of 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds. Chin. J. Synthetic Chem., 2012, 20, 137-142.
[25]
Li, H.; Sun, L.; Li, H.; Lv, X.; Semukunzi, H.; Li, R.; Yu, J.; Yuan, S.; Lin, S. DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells. Cell Death Dis., 2017, 8(5)e2810
[26]
Wang, X.; Wang, H.; Zhang, C.; Zhang, K. Experimental study on inhibition of S180 tumor cells by Agrimonia pilosa extract. Afr. J. Trad. Comp. Altern. Med., 2013, 10(3), 475-479.
[27]
Du, H.; Liu, Y.; Chen, X.; Yu, X.; Hou, X.; Li, H.; Zhan, M.; Lin, S.; Lu, L.; Yuan, S.; Sun, L. DT-13 synergistically potentiates the sensitivity of gastric cancer cells to topotecan via cell cycle arrest in vitro and in vivo. Eur. J. Pharmacol., 2018, 818, 124-131.
[28]
Glisson, B.S.; Ross, W.E. DNA topoisomerase II: A primer on the enzyme and its unique role as a multidrug target in cancer chemotherapy. Pharmacol. Ther., 1987, 32(2), 89-106.
[29]
Turinetto, V.; Pardini, B.; Allione, A.; Fiorito, G.; Viberti, C.; Guarrera, S.; Russo, A.; Anglesio, S.; Ruo Redda, M.G.; Casetta, G.; Cucchiarale, G.; Destefanis, P.; Oderda, M.; Gontero, P.; Rolle, L.; Frea, B.; Vineis, P.; Sacerdote, C.; Giachino, C.; Matullo, G. H2AX phosphorylation level in peripheral blood mononuclear cells as an event-free survival predictor for bladder cancer. Mol. Carcinog., 2016, 55(11), 1833-1842.
[30]
Georgieva, M.; Rashydov, N.M.; Hajduch, M. DNA damage, repair monitoring and epigenetic DNA methylation changes in seedlings of Chernobyl soybeans. DNA Repair., 2017, 50, 14-21.
[31]
Weimer, A.K.; Biedermann, S.; Schnittger, A. Specialization of CDK regulation under DNA damage. Cell Cyc, 2017, 16(2), 143-144.
[32]
Zhang, Y.; Zhang, R.; Ding, X.; Peng, B.; Wang, N.; Ma, F.; Peng, Y.; Wang, Q.; Chang, J. FNC efficiently inhibits mantle cell lymphoma growth. PloS One, 2017, 12(3)e0174112
[33]
Chen, H.; Zeng, X.; Gao, C.; Ming, P.; Zhang, J.; Guo, C.; Zhou, L.; Lu, Y.; Wang, L.; Huang, L.; He, X.; Mei, L. A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity. Sci. Rep., 2015, 5, 10893.
[34]
Hamdan, M.; Jones, K.T.; Cheong, Y.; Lane, S.I. The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis. Sci. Rep., 2016, 6, 36994.
[35]
Shigetomi, H.; Oonogi, A.; Tsunemi, T.; Tanase, Y.; Yamada, Y.; Kajihara, H.; Yoshizawa, Y.; Furukawa, N.; Haruta, S.; Yoshida, S.; Sado, T.; Oi, H.; Kobayashi, H. The role of components of the chromatin modification machinery in carcinogenesis of clear cell carcinoma of the ovary (Review). Oncol. Lett., 2011, 2(4), 591-597.
[36]
Khanna, K.K.; Jackson, S.P. DNA double-strand breaks: Signaling, repair and the cancer connection. Nat. Genet., 2001, 27(3), 247-254.
[37]
Carroll, B.; Donaldson, J.C.; Obeid, L. Sphingolipids in the DNA damage response. Adv. Biol. Regul., 2015, 58, 38-52.
[38]
Martin, J.S.; Winkelmann, N.; Petalcorin, M.I.; McIlwraith, M.J.; Boulton, S.J. RAD-51-dependent and -independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair. Mol. Cell. Biol., 2005, 25(8), 3127-3139.
[39]
Ewald, B.; Sampath, D.; Plunkett, W. ATM and the Mre11-Rad50-Nbs1 complex respond to nucleoside analogue-induced stalled replication forks and contribute to drug resistance. Canc Res., 2008, 68(19), 7947-7955.
[40]
Zhao, W.T.; Wang, Y.T.; Huang, Z.W.; Fang, J. BRCA2 affects the efficiency of DNA double-strand break repair in response to N-nitroso compounds with differing carcinogenic potentials. Oncol. Lett., 2013, 5(6), 1948-1954.
[41]
Aikemu, A.; Umar, A.; Yusup, A.; Upur, H.; Berke, B.; Begaud, B.; Moore, N. Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice. BMC Complement. Altern. Med., 2012, 12, 157.

Rights & Permissions Print Cite
Article Metrics
62
5
© 2024 Bentham Science Publishers | Privacy Policy