Skip to main content

Advertisement

Log in

Cytotoxic effect, antitumour activity and toxicity of organotin derivatives with ortho- or para-hydroxy-benzoic acids

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

The cytotoxic and antitumour activities of five organotin complexes (15) with o-hydroxy-benzoic or p-hydroxy-benzoic acids were evaluated in a series of in vitro and in vivo experiments. All complexes exhibited strong cytotoxic activity against all cancer cells lines, whereas complexes 1, 2 and 4 induced apoptosis at significantly lower doses than complexes 3 and 5. Human cancer cells treated with increasing concentrations of complexes 1, 2 and 4 gradually lost their ability to form colonies. Only complexes 1 and 2 inhibited colony formation efficiency in rat leiomyosarcoma cells. Histopathology of liver and kidney showed mild damage and lung oedema after a single injection of 10 mg/kg body wt of complex 1 to Wistar rats. At higher doses (100 mg/kg body wt) brain stem oedema was observed. Daily administration of tumour-bearing Wistar rats (leiomyosarcoma) with 1 mg/kg body wt of complex 1 until death reduced the mean tumour growth rate by more than 3× fold and prolonged mean survival time by 120%. These findings indicate that the organotin complexes with ortho- or para-hydroxy-benzoic acids possess potent cytotoxic and antitumour activity and they could be used as potential chemotherapeutic agents.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  • Abdellah MA, Hadjikakou SK, Hadjiliadis N, Kubicki M, Bakas T, Kourkoumelis N, Simos YV, Karkabounas S, Barsan MM, Butler IS (2009) Synthesis, characterization, and biological studies of organotin(IV) derivatives with o- or p-hydroxybenzoic acids. Bioinorg Chem Appl 2009:542979

    Article  PubMed Central  Google Scholar 

  • Alama A, Tasso B, Novelli F, Sparatore F (2009) Organometallic compounds in oncology: implications of novel organotins as antitumor agents. Drug Discov Today 14:500–508

    Article  CAS  PubMed  Google Scholar 

  • Amir MK, Khan S, Rehman Z, Shah A, Butler IS (2014) Anticancer activity of organotin(IV) carboxylates. Inorg Chim Acta 423:14–25

    Article  CAS  Google Scholar 

  • Arjmand F, Parveen S, Tabassum S, Pettinari C (2014) Organo-tin antitumor compounds: Their present status in drug development and future perspectives. Inorg Chim Acta 423:26–37

    Article  CAS  Google Scholar 

  • Avdikos A, Karkabounas S, Metsios A, Kostoula O, Havelas K, Binolis J, Verginadis I, Hatziaivazis G, Simos I, Evangelou A (2007) Anticancer effects on leiomyosarcoma-bearing Wistar rats after electromagnetic radiation of resonantradiofrequencies. Hell J Nucl Med 10:95–101

    PubMed  Google Scholar 

  • Aw TY, Nicotera P, Manzo L, Orrenius S (1990) Tributiltin stimulates apoptosis in rats thymocytes. Arch Biochem Biophys 283:46–50

    Article  CAS  PubMed  Google Scholar 

  • Boyer IJ (1989) Toxicity of dibutyltin, tributyltin and other organotin compounds to humans and to experimental animals. Toxicology 55:253–298

    Article  CAS  PubMed  Google Scholar 

  • Cai J, Wang M, Li B, Wang C, Chen Y, Zuo Z (2009) Apoptotic and necrotic action mechanisms of trimethyltin in human hepatoma G2 (HepG2) cells. Chem Res Toxicol 22:1582–1587

    Article  CAS  PubMed  Google Scholar 

  • Chasapis CT, Hadjikakou SK, Garoufis A, Hadjiliads N, Bakas T, Kubicki M, Ming Y (2004) Organotin(IV) derivatives of L-cysteine and their in vitro anti-tumor properties. Bioinorg Chem Appl 2004:43–54

    Article  Google Scholar 

  • Dokorou V, Primikiri A, Kovala-Demertzi D (2011) The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents. J Inorg Biochem 105:195–201

    Article  CAS  PubMed  Google Scholar 

  • Garbutcheon-Singh KB, Grant MP, Harper BW, Krause-Heuer AM, Manohar M, Orkey N, Aldrich-Wright JR (2011) Transition metal based anticancer drugs. Curr Top Med Chem 11:521–542

    Article  CAS  PubMed  Google Scholar 

  • Gielen M (1995) Tin-based antitumour drugs: new developments. Met Based Drugs 2:99–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gielen M, de Vos D, Meriem A, Boualam M, el Khloufi A, Willem R (1993) The acute toxicity and in vivo antitumour activity against L1210 leukemia of triphenyltin 3,5-diisopropylsalicylate, bis (di-n-butyl-(s)-2-pyrrolidone-5-carboxylato)tin oxide and di-n-butyltin bis(3-amino-4-methylbenzoate). Vivo 7:171–174

    CAS  Google Scholar 

  • Grondin M, Marion M, Denizeau F, Averill-Bates DA (2007) Tributyltin induces apoptotic signaling in hepatocytes through pathways involving the endoplasmic reticulum and mitochondria. Toxicol Appl Pharmacol 222:57–68

    Article  CAS  PubMed  Google Scholar 

  • Höti N, Ma J, Tabassum S, Wang Y, Wu M (2003) Triphenyl tin benzimidazolethiol, a novel antitumor agent, induces mitochondrial-mediated apoptosis in human cervical cancer cells via suppression of HPV-18 encoded E6. J Biochem 134:521–528

    Article  PubMed  Google Scholar 

  • Köberle B, Tomicic MT, Usanova S, Kaina B (2010) Cisplatin resistance: preclinical findings and clinical implications. Biochim Biophys Acta 1806:172–182

    PubMed  Google Scholar 

  • Liu HG, Wang Y, Lian L, Xu LH (2006) Tributiltin induces DNA damage as well as oxidative damage in rats. Environ Toxicol 21:166–171

    Article  CAS  PubMed  Google Scholar 

  • Matsuno-Yagi A, Hatefi Y (1993) Studies on the mechanism of oxidative phosphorylation. ATP synthesis by submitochondrial particles inhibited at F0 by venturicidin and organotin compounds. J Biol Chem 268:6168–6173

    CAS  PubMed  Google Scholar 

  • Metsios A, Verginadis I, Simos Y, Batistatou A, Peschos D, Ragos V, Vezyraki P, Evangelou A, Karkabounas S (2012) Cytotoxic and anticancer effects of the triorganotin compound [(C6H5)3Sn(cmbzt)]: an in vitro, ex vivo and in vivo study. Eur J Pharm Sci 47:490–496

    Article  CAS  PubMed  Google Scholar 

  • Miller RO, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2(11):2490–2518

    Article  CAS  Google Scholar 

  • Muhammad N, Guo Z (2014) Metal-based anticancer chemotherapeutic agents. Curr Opin Chem Biol 19:144–153

    Article  CAS  PubMed  Google Scholar 

  • Nakatsu Y, Kotake Y, Ohta S (2007) Concentration dependence of the mechanisms of tributyltin-induced apoptosis. Toxicol Sci 97:438–447

    Article  CAS  PubMed  Google Scholar 

  • Reader S, Moutardier V, Denizeau F (1999) Tributyltin triggers apoptosis in trout hepatocytes: the role of Ca2+, protein kinase C and proteases. Biochim Biophys Acta 1448:473–485

    Article  CAS  PubMed  Google Scholar 

  • Ross M, Gielen M, Lelieveld P, De Vos D (1991) Cytotoxic activity of di-n-butyltin(IV)(X-A-B-Y) compounds related to salicylic acid against human tumour cells. Anticancer Res 11:1089–1091

    CAS  PubMed  Google Scholar 

  • Tada-Oikawa S, Kato T, Kuribayashi K, Nishino K, Murata M, Kawanishi S (2008) Critical role of hydrogen peroxide in the differential susceptibility of Th1 and Th2 cells to tributyltin-induced apoptosis. Biochem Pharmacol 75:552–561

    Article  CAS  PubMed  Google Scholar 

  • Verginadis II, Karkabounas S, Simos Y, Kontargiris E, Hadjikakou SK, Batistatou A, Evangelou A, Charalabopoulos K (2011) Anticancer and cytotoxic effects of a triorganotin compound with 2-mercapto-nicotinic acid in malignant cell lines and tumor bearing Wistar rats. Eur J Pharm Sci 42:253–261

    Article  CAS  PubMed  Google Scholar 

  • Viviani B, Rossi AD, Chow SC, Nicotera P (1995) Organotin compounds induce calcium overload and apoptosis in PC12 cells. Neurotoxicology 16:19–25

    CAS  PubMed  Google Scholar 

  • Winship KA (1988) Toxicity of tin and its compounds. Advers Drug React Acute Poison Rev 7:19–38

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yannis V. Simos or Dimitrios Peschos.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Agiorgiti, M.S., Evangelou, A., Vezyraki, P. et al. Cytotoxic effect, antitumour activity and toxicity of organotin derivatives with ortho- or para-hydroxy-benzoic acids. Med Chem Res 27, 1122–1130 (2018). https://doi.org/10.1007/s00044-018-2135-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-018-2135-7

Keywords

Navigation