Skip to main content

Advertisement

SpringerLink
Log in

A novelly synthesized phenanthroline derivative is a promising DNA-damaging anticancer agent inhibiting G1/S checkpoint transition and inducing cell apoptosis in cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The study mainly aimed to determine the biological function of a novelly synthesized phenanthroimidazole derivative, named L233, and to explore its potential mechanisms.

Methods

Cell survival was examined using the MTT assays, and the DNA-damaging role of L233 was explored using the comet assay. Moreover, the western blotting assays and immunofluorescence assays were used to detect DNA damage biomarkers. Afterward, the flow cytometry was used to assess the effects of L233 on cell cycle distribution. As for the detection of cell apoptosis upon L233 treatment, the Hoechst 33342 staining, flow cytometry, and western blotting assays were all put into practice.

Results

We find that L233 inhibits tumor cell growth more efficiently and safely than cisplatin. Moreover, it is a DNA-damaging agent, interrupting the cell cycle G1/S checkpoint transition and inducing cell apoptosis by not only activating ATM/CHK1 signaling pathway, but also targeting CHK1 to reduce the expression of RAP80 and PARP-1 to compromise the DNA damage repair in tumor cells.

Conclusions

In summary, L233 is a promising anticancer drug for the development of novel chemotherapies in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Goto H, Izawa I, Li P, Inagaki M (2012) Novel regulation of checkpoint kinase 1: is checkpoint kinase 1 a good candidate for anti-cancer therapy? Cancer Sci 103:1195–1200

    Article  PubMed  CAS  Google Scholar 

  2. Medema RH, Macurek L (2012) Checkpoint control and cancer. Oncogene 31:2601–2613

    Article  PubMed  CAS  Google Scholar 

  3. Langerak P, Russell P (2011) Regulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair. Philos Trans R Soc Lond B Biol Sci 366:3562–3571

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Niida H, Nakanishi M (2006) DNA damage checkpoints in mammals. Mutagenesis 21:3–9

    Article  PubMed  CAS  Google Scholar 

  5. Zhao H, Piwnica-Worms H (2001) Atr-mediated checkpoint pathways regulate phosphorylation and activation of human chk1. Mol Cell Biol 21:4129–4139

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Smith J, Tho LM, Xu N, Gillespie DA (2010) The atm-chk2 and atr-chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res 108:73–112

    Article  PubMed  CAS  Google Scholar 

  7. Skladanowski A, Bozko P, Sabisz M (2009) DNA structure and integrity checkpoints during the cell cycle and their role in drug targeting and sensitivity of tumor cells to anticancer treatment. Chem Rev 109:2951–2973

    Article  PubMed  CAS  Google Scholar 

  8. Do K, Doroshow JH, Kummar S (2013) Wee1 kinase as a target for cancer therapy. Cell Cycle 12:3159–3164

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Weiss GJ, Donehower RC, Iyengar T, Ramanathan RK, Lewandowski K, Westin E, Hurt K, Hynes SM, Anthony SP, McKane S (2013) Phase I dose-escalation study to examine the safety and tolerability of ly2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer. Invest New Drugs 31:136–144

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Ma CX, Ellis MJ, Petroni GR, Guo Z, Cai SR, Ryan CE, Craig Lockhart A, Naughton MJ, Pluard TJ, Brenin CM et al (2013) A phase II study of ucn-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat 137:483–492

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Sausville E, Lorusso P, Carducci M, Carter J, Quinn MF, Malburg L, Azad N, Cosgrove D, Knight R, Barker P et al (2014) Phase I dose-escalation study of azd7762, a checkpoint kinase inhibitor, in combination with gemcitabine in us patients with advanced solid tumors. Cancer Chemother Pharmacol 73:539–549

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Seto T, Esaki T, Hirai F, Arita S, Nosaki K, Makiyama A, Kometani T, Fujimoto C, Hamatake M, Takeoka H et al (2013) Phase I, dose-escalation study of azd7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol 72:619–627

    Article  PubMed  CAS  Google Scholar 

  13. Sun DD, Wang WZ, Mao JW, Mei WJ, Liu J (2012) Imidazo [4,5f][1,10] phenanthroline derivatives as inhibitor of c-myc gene expression in a549 cells via nf-kappab pathway. Bioorg Med Chem Lett 22:102–105

    Article  PubMed  CAS  Google Scholar 

  14. Liao S, Zhang Z, Wu Q, Wang X, Mei W (2014) Microwave-assisted synthesis of phenanthroimidazole derivatives as stabilizer of c-myc g-quadruplex DNA. Bioorg Med Chem 22:6503–6508

    Article  PubMed  CAS  Google Scholar 

  15. Suntharalingam K, Leczkowska A, Furrer MA, Wu Y, Kuimova MK, Therrien B, White AJ, Vilar R (2012) A cyclometallated platinum complex as a selective optical switch for quadruplex DNA. Chemistry 18:16277–16282

    Article  PubMed  CAS  Google Scholar 

  16. Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002) Direct evidence for a g-quadruplex in a promoter region and its targeting with a small molecule to repress c-myc transcription. Proc Natl Acad Sci USA 99:11593–11598

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Krosniak M, Kowalska J, Francik R, Grybos R, Kwiatek WM (2014) Effects of vanadium complexes supplementation on v, cu, mn, k, fe, zn, and ca concentration in stz diabetic rats pancreas. Acta Pol Pharm 71:583–592

    PubMed  CAS  Google Scholar 

  18. Krosniak M, Francik R, Kowalska J, Grybos R, Blusz M, Kwiatek WM (2013) Effects of vanadium complexes supplementation on v, fe, cu, zn, mn, ca and k concentration in stz diabetic rat’s spleen. Acta Pol Pharm 70:71–77

    PubMed  CAS  Google Scholar 

  19. Yodoshi M, Odoko M, Okabe N (2007) Structures and DNA-binding and cleavage properties of ternary copper(ii) complexes of glycine with phenanthroline, bipyridine, and bipyridylamine. Chem Pharm Bull 55:853–860

    Article  PubMed  CAS  Google Scholar 

  20. Geric M, Gajski G, Garaj-Vrhovac V (2014) Gamma-h2ax as a biomarker for DNA double-strand breaks in ecotoxicology. Ecotoxicol Environ Saf 105:13–21

    Article  PubMed  CAS  Google Scholar 

  21. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007) Rnf8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131:887–900

    Article  PubMed  CAS  Google Scholar 

  22. Cortes-Gutierrez EI, Hernandez-Garza F, Garcia-Perez JO, Davila-Rodriguez MI, Aguado-Barrera ME, Cerda-Flores RM (2012) Evaluation of DNA single and double strand breaks in women with cervical neoplasia based on alkaline and neutral comet assay techniques. J Biomed Biotechnol 2012:385245

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang B (2014) Analyzing cell cycle checkpoints in response to ionizing radiation in mammalian cells. Methods Mol Biol 1170:313–320

    Article  PubMed  Google Scholar 

  24. Lamkanfi M, Kanneganti TD (2010) Caspase-7: a protease involved in apoptosis and inflammation. Int J Biochem Cell Biol 42:21–24

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Yin W, Nie Y, Zhang Z, Xie L, He X (2015) Mir-193b acts as a cisplatin sensitizer via the caspase-3-dependent pathway in hcc chemotherapy. Oncol Rep 34:368–374

    PubMed  Google Scholar 

  26. Wu C, Geng X, Wan S, Hou H, Yu F, Jia B, Wang L (2015) Cecropin-p17, an analog of cecropin b, inhibits human hepatocellular carcinoma cell hepg-2 proliferation via regulation of ros, caspase, bax, and bcl-2. J Pept Sci Off Publ Eur Pept Soc 21:661–668

    CAS  Google Scholar 

  27. Martin M, Terradas M, Tusell L, Genesca A (2012) Atm and DNA-pkcs make a complementary couple in DNA double strand break repair. Mutat Res 751:29–35

    Article  CAS  Google Scholar 

  28. Davis AJ, So S, Chen DJ (2010) Dynamics of the pi3 k-like protein kinase members atm and DNA-pkcs at DNA double strand breaks. Cell Cycle 9:2529–2536

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z (2010) Usp10 regulates p53 localization and stability by deubiquitinating p53. Cell 140:384–396

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Kim KS, Heo JI, Choi KJ, Bae S (2014) Enhancement of cellular radiation sensitivity through degradation of chk1 by the xiap-xaf1 complex. Cancer Biol Ther 15:1622–1634

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Park C, Suh Y, Cuervo AM (2015) Regulated degradation of chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun 6:6823

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. O’Grady S, Finn SP, Cuffe S, Richard DJ, O’Byrne KJ, Barr MP (2014) The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev 40:1161–1170

    Article  PubMed  Google Scholar 

  33. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378

    Article  PubMed  CAS  Google Scholar 

  34. Ding J, Miao ZH, Meng LH, Geng MY (2006) Emerging cancer therapeutic opportunities target DNA-repair systems. Trends Pharmacol Sci 27:338–344

    Article  PubMed  CAS  Google Scholar 

  35. Passananti C, Fanciulli M (2007) The anti-apoptotic factor che-1/aatf links transcriptional regulation, cell cycle control, and DNA damage response. Cell Div 2:21

    Article  PubMed  PubMed Central  Google Scholar 

  36. Imreh G, Norberg HV, Imreh S, Zhivotovsky B (2011) Chromosomal breaks during mitotic catastrophe trigger gammah2ax-atm-p53-mediated apoptosis. J Cell Sci 124:2951–2963

    Article  PubMed  CAS  Google Scholar 

  37. Min W, Bruhn C, Grigaravicius P, Zhou ZW, Li F, Kruger A, Siddeek B, Greulich KO, Popp O, Meisezahl C et al (2013) Poly(adp-ribose) binding to chk1 at stalled replication forks is required for s-phase checkpoint activation. Nat Commun 4:2993

    PubMed  Google Scholar 

  38. Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA (2009) The rap80-brcc36 de-ubiquitinating enzyme complex antagonizes rnf8-ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci USA 106:3166–3171

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Yang Q, Ou C, Liu M, Xiao W, Wen C, Sun F (2014) Nrage promotes cell proliferation by stabilizing pcna in a ubiquitin-proteasome pathway in esophageal carcinomas. Carcinogenesis 35:1643–1651

    Article  PubMed  CAS  Google Scholar 

  40. Yang Q, Zhang Z, Mei W, Sun F (2014) A novel ruthenium(ii)-polypyridyl complex inhibits cell proliferation and induces cell apoptosis by impairing DNA damage repair. J Chemother 26:235–242

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study is funded by Shanghai Young Science and Technology Talents Sailing Program (Grant No. 15YF1409300) and Natural Science Foundation of China (Grant No. 81272292, 81071524, 81171778, 81371913, 81472624, 31171086, and 81472124).

Author contributions

Yongchun Yu and Wenjie Mei conceived and supervised the study; Ni Zhen and Qingyuan Yang designed experiments; Ni Zhen, Qingyuan Yang, Qiong Wu, Xinyi Zhu, Yue Wang, and Fenyong Sun performed experiments; Yongchun Yu, Ni Zhen, and Qingyuan Yang analyzed the data; Qingyuan Yang and Ni Zhen wrote the manuscript; Yongchun Yu and Wenjie Mei revised the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Clinical Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, 200072, China

      Ni Zhen, Qingyuan Yang, Xinyi Zhu, Yue Wang & Fenyong Sun

    2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510405, China

      Qiong Wu & Wenjie Mei

    3. Central Laboratory, Shanghai Chinese Medicine Hospital, Shanghai, 200071, China

      Yongchun Yu

    Authors
    1. Ni Zhen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Qingyuan Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Qiong Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xinyi Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yue Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Fenyong Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Wenjie Mei
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Yongchun Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Wenjie Mei or Yongchun Yu.

    Ethics declarations

    Conflict of interest

    All the authors declare no conflicts of interest.

    Additional information

    N. Zhen and Q. Yang have contributed equally to the study.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    280_2015_2894_MOESM1_ESM.tif

    Figure S1. A-B. L233, firstly stored at -20 oC for half a year, was further stored at 4 oC and -80 oC for one (A) or two weeks (B), respectively, and then was subjected to MTT assays to detect its anticancer activity. (TIFF 281 kb)

    280_2015_2894_MOESM2_ESM.tif

    Figure S2. A-B. Eca-109 (A) and SMMC-7721 (B) were treated with indicated concentrations of L233 complex for 24 h and lysed to detect the indicated apoptotic proteins using Western blot assays. (TIFF 1122 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhen, N., Yang, Q., Wu, Q. et al. A novelly synthesized phenanthroline derivative is a promising DNA-damaging anticancer agent inhibiting G1/S checkpoint transition and inducing cell apoptosis in cancer cells. Cancer Chemother Pharmacol 77, 169–180 (2016). https://doi.org/10.1007/s00280-015-2894-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00280-015-2894-5

    Keywords

    Search

    Navigation