Skip to main content

Advertisement

SpringerLink
Log in

Cytotoxic and apoptotic effects of synthetic benzochromene derivatives on human cancer cell lines

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

With the aim of discovering potential cytotoxic agents, a series of benzochromene derivatives were screened for their cytotoxic activity against seven human cancer cell lines by standard 3-(4, 5-dimethyl thiazol)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis, as the mechanism of cell death, was investigated morphologically by acridine orange/ethidium bromide staining and cell surface expression assay of phosphatidylserine by Annexin V-PE/7-AAD technique. The effects of compounds on reactive oxygen species (ROS) and nitric oxide (NO) generations in three human breast cancer cell lines were also studied. All compounds showed significant cytotoxic activity with inhibitory concentration (IC50) values in the micromolar range (4.6–21.5 μM). The results of apoptosis evaluation suggested that the cytotoxic activity of these compounds in breast cancer cells occurs via apoptosis. MCF-7 cell line showed higher levels of ROS and NO production after treatment with compounds. The increase in ROS production after 4 and 24 h indicated that one of the ways that these compounds can induce apoptosis is by increasing ROS generation. Cytotoxic and apoptotic effects of these compounds in human cancer cells indicated that they can be a good candidate for further pharmacological studies to discover effective anticancer agents.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Augstein J, Cairns H, Chambers A, Burns JW, Radziwonik H (1976) 6,8-Di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid: a chromone derivative with anti-allergic, anti-inflammatory and uricosuric activity. J Pharm Pharmacol 28:919–920, PMID:12270

    Article  CAS  PubMed  Google Scholar 

  • Bedair AH, El-Hady NA, El-Latif A, Fakery AH, El-Agrody AM (2000) 4-Hydroxycoumarin in heterocyclic synthesis. Part III. Synthesis of some new pyrano[2,3-d]pyrimidine, 2-substitute. Farmaco 55:708–714, PMID:11204946

    Article  CAS  PubMed  Google Scholar 

  • Benhar M, Engelberg D, Levitzki A (2002) ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 3:420–425, PMID:11991946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 92:7162–7166, PMID:7638161

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brodská B, Holoubek A (2011) Generation of reactive oxygen species during apoptosis induced by DNA-damaging agents and/or histone deacetylase inhibitors. Oxid Med Cell Longev 2011:253529. doi:10.1155/2011/253529

    Article  PubMed Central  PubMed  Google Scholar 

  • Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130, PMID:8466628

    Article  CAS  PubMed  Google Scholar 

  • Conklin KA (2004) Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integ Cancer Ther 3:294–300

    Article  CAS  Google Scholar 

  • Dell CP, Smith CW (1993) European Patent Appl. EP 537949. Chem Abstr 119:139102d, PMID:15523100

    Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516, PMID:17562483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • England K, Driscoll CO, Cotter TG (2006) ROS and protein oxidation in early stages of cytotoxic drug induced apoptosis. Free Radic Res 40:1124–1137, PMID:17050166

    Article  CAS  PubMed  Google Scholar 

  • Geller DA, Billiar TR (1998) Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 17:7–23, PMID:9544420

    Article  CAS  PubMed  Google Scholar 

  • Hannun YA (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89:1845–1853, PMID:9058703

    CAS  PubMed  Google Scholar 

  • Huang P, Robertson LE, Wright S, Plunkett W (1995) High molecular weight DNA fragmentation: a critical event in nucleoside analogue-induced apoptosis in leukemia cells. Clin Cancer Res 1:1005–1013, PMID:9816073

    CAS  PubMed  Google Scholar 

  • Huerta S, Chilka S, Bonavida B (2008) Nitric oxide donors: novel cancer therapeutics (review). Int J Oncol 33:909–927, PMID:18949354

    CAS  PubMed  Google Scholar 

  • Khafagy MM, Abd El-Wahab AHF, Eid FA, El-Agrody AM (2002) Synthesis of halogen derivatives of benzo[h]chromene and benzo[a]anthracene with promising antimicrobial activities. Farmaco 57:715–722, PMID:12385521

    Article  CAS  PubMed  Google Scholar 

  • Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, Van Oers MH (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:1415–1420, PMID:8068938

    CAS  PubMed  Google Scholar 

  • Lampiasi N, Azzolina A, D’Alessandro N et al (2009) Antitumor effects of dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, in human liver cancer cells are mediated through a reactive oxygen species-dependent mechanism. Mol Pharmacol 76:290–300. doi:10.1124/mol.109.055418, PMID:19461054

    Article  CAS  PubMed  Google Scholar 

  • LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231, PMID:1322737

    Article  CAS  PubMed  Google Scholar 

  • Longobardi M, Bargagna A, Mariani E et al (1990) 2H-[1] benzothiepino [5, 4-b] pyran derivatives with local anesthetic and antiarrhythmic activities. Farmaco 45:399–404, PMID:2400514

    CAS  PubMed  Google Scholar 

  • Lu Y, Mahato RI (2009) Pharmaceutical perspectives of cancer therapeutics. In: Narang AS, Desai DS (eds) Anticancer drug development. Springer, New York, pp 49–92

    Google Scholar 

  • Mahdavi M, Davoodi J, Zali MR, Foroumadi A (2011) Concomitant activation of caspase-9 and down- regulation of IAP proteins as a mechanism of apoptotic death in HepG2, T47D and HCT-116 cells upon exposure to a derivative from 4-aryl-4H-chromenes family. Biomed Pharmacother 65:175–182. doi:10.1016/j.biopha.2011.03.001, PMID:21565459

    Article  CAS  PubMed  Google Scholar 

  • Meshkini A, Yazdanparast R (2012) Involvement of oxidative stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells. Exp Toxicol Pathol 64:357–365. doi:10.1016/j.etp.2010.09.010, PMID:21074392

    Article  CAS  PubMed  Google Scholar 

  • Mohr SJ, Chirigos MA, Fuhrman FS, Pryor JW (1975) Pyran copolymer as an effective adjuvant to chemotherapy against a murine leukemia and solid tumor. Cancer Res 35:3750–3754, PMID:1192431

    CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63, PMID:6606682

    Article  CAS  PubMed  Google Scholar 

  • Musa MA, Badisa VLD, Latinwo LM, Waryoba C, Ugochukwu N (2010) In vitro cytotoxicity of benzopyranone derivatives with basic side chain against human lung cell lines. Anticancer Res 30:4613–4617, PMID:21115914

    CAS  PubMed Central  PubMed  Google Scholar 

  • Naimi-Jamal MR, Mashkouri S, Sharifi A (2010) An efficient, multicomponent approach for solvent-free synthesis of 2-amino-4H-chromene scaffold. Mol Divers 14:473–477. doi:10.1007/s11030-010-9246-5, PMID:20373141

    Article  CAS  PubMed  Google Scholar 

  • O'Kennedy R, Thornes RD (1997) Coumarins: biology, applications, and mode of action. Wiley, New York, Chichester

    Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108, PMID:15761078

    Article  PubMed  Google Scholar 

  • Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389:300–305, PMID:9305847

    Article  CAS  PubMed  Google Scholar 

  • Sarih M, Souvannavong V, Adam A (1993) Nitric oxide synthase induces macrophage death by apoptosis. Biochem Biophys Res Commun 191:503–508, PMID:7681667

    Article  CAS  PubMed  Google Scholar 

  • Safavi M, Esmati N, Ardestani SK, Emami S, Ajdari S, Davoodi J, Shafiee A, Foroumadi A (2012) Halogenated flavanones as potential apoptosis-inducing agents: synthesis and biological activity evaluation. Eur J Med Chem 58:573–580. doi:10.1016/j.ejmech.2012.10.043

    Article  CAS  PubMed  Google Scholar 

  • Satchell PG, Gutmann JL, Witherspoon DE (2003) Apoptosis: an introduction for the endodontist. Int Endod J 36:237–245, PMID:12702117

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Zhang X, Broderick M, Fein H (2003) Measurement of nitric oxide production in biological systems by using Griess reaction assay. Sensors 3:276–284. doi:10.3390/s30800276

    Article  CAS  Google Scholar 

  • Thomsen LL, Miles DW (1998) Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev 17:107–118, PMID:9544426

    Article  CAS  PubMed  Google Scholar 

  • Tolcher AW (2002) Regulators of apoptosis as anticancer targets. Hematol Oncol Clin North Am 16:1255–1267, PMID:12512391

    Article  PubMed  Google Scholar 

  • Tsai SH, Lin-Shiau SY, Lin JK (1999) Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Br J Pharmacol 126:673–680, PMID:10188978

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Van Rensburg H, Van Heerden PS, Bezuidenhoudt BCB, Ferreira D (1997) Enantioselective synthesis of the four catechin diastereomer derivatives. Tetrahedron Lett 38:3089–3092. doi:10.1016/S0040-4039(97)00552- 2

    Article  Google Scholar 

  • Wink DA, Cook JA, Christodoulou D, Krishna MC, Pacelli R, Kim S, DeGraff W, Gamson J, Vodovotz Y, Russo A, Mitchell JB (1997) Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin. Nitric Oxide 1:88–94, PMID: 9701048

    Article  CAS  PubMed  Google Scholar 

  • Xie K, Huang S (2003) Contribution of nitric oxide-mediated apoptosis to cancer metastasis inefficiency. Free Radic Biol Med 34:969–986, PMID:12684082

    Article  CAS  PubMed  Google Scholar 

  • Xie KP, Huang SY, Dong ZY, Fidler IJ (1993) Cytokine induced apoptosis in transformed murine fibroblasts involves synthesis of endogenous nitric-oxide. Int J Oncol 3:1043–1048, PMID:21573470

    CAS  PubMed  Google Scholar 

  • Zhang H-Z, Kasibhatla S, Kuemmerle J et al (2005) Discovery and structure-activity relationship of 3-aryl-5-aryl-1, 2, 4-oxadiazoles as a new series of apoptosis inducers and potential anticancer agents. J Med Chem 48:5215–5223, PMID:16078840

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Asma Kheirollahi, Mahboobeh Pordeli & Sussan Kabudanian Ardestani

  2. Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, 33535-111, Iran

    Maliheh Safavi

  3. Organic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846, Iran

    Sara Mashkouri & M. Reza Naimi-Jamal

Authors
  1. Asma Kheirollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahboobeh Pordeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maliheh Safavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Mashkouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Reza Naimi-Jamal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sussan Kabudanian Ardestani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sussan Kabudanian Ardestani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kheirollahi, A., Pordeli, M., Safavi, M. et al. Cytotoxic and apoptotic effects of synthetic benzochromene derivatives on human cancer cell lines. Naunyn-Schmiedeberg's Arch Pharmacol 387, 1199–1208 (2014). https://doi.org/10.1007/s00210-014-1038-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-014-1038-5

Keywords

Search

Navigation