Skip to main content
SpringerLink
Log in

Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The cytotoxic activity of thiosemicarbazones (TSC) and thiocarbohydrazones was investigated against the MelRm melanoma cell line. In general, the melanoma line was susceptible to metal coordinating agents, the most useful of which incorporated the dipyridyl ketone hydrazone sub-structure. The impact of copper supplementation on the cytotoxic activity towards the melanoma line (MelRm) of metal coordinating agents when acting as ionophores is less predictable than the general improvement that has been seen in other cancer cells such as breast adenocarcinoma (MCF-7). The bimetallic nature of thiocarbohydrazone complexes with resultant loss of lipophilicity is a limiting factor in usage against MelRm. The cytotoxic activity of TSC against MelRm when used as copper ionophores could be markedly improved through combination with a partner drug capable of disrupting cellular defences to oxidative stress. In the absence of copper supplementation, both TSC and thiocarbohydrazones could be used to initiate cell cycle arrest and this could be employed to improve cytotoxicity profiles of other metallodrugs such as cisplatin.

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
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Akladios FN, Andrew SD, Parkinson CJ (2015) Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis. Bioorg Med Chem 23:3097–3104

    Article  CAS  PubMed  Google Scholar 

  • Akladios FN, Andrew SD, Parkinson CJ (2016) Improved cytotoxicity of pyridyl-substituted thiosemicarbazones against MCF-7 when used as metal ionophores. Biometals 29(1):157–170

    Article  CAS  PubMed  Google Scholar 

  • Bacchi A, Carcelli M, Pelagatti P, Pelizzi C, Pelizzi G, Zani F (1999) Antimicrobial and mutagenic activity of some carbono-and thiocarbonohydrazone ligands and their copper (II), iron (II) and zinc (II) complexes. J Inorg Biochem 75(2):123–133

    Article  CAS  PubMed  Google Scholar 

  • Becker EM, Lovejoy DB, Greer JM, Watts R, Richardson DR (2003) Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumour agents. Br J Pharmacol 138(5):819–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernhardt PV, Caldwell LM, Chaston TB, Chin P, Richardson DR (2003) Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues. J Biol Inorg Chem 8:866–880

    Article  CAS  PubMed  Google Scholar 

  • Blatt J, Stitely S (1987) Antineuroblastoma activity of desferoxamine in human cell lines. Cancer Res 47(7):1749–1750

    CAS  PubMed  Google Scholar 

  • Bogojeski J, Petrović B, Bugarčić ŽD (2012) Interactions of the platinum (II) complexes with nitrogen-and sulfur-bonding bio-molecules. In: Oppezzo P. (ed) Chronic lymphocytic leukemia. InTech. doi:10.5772/1156

  • Bustos C, Burckhardt O, Schrebler R, Carrillo D, Arif A, Cowley A, Nunn C (1990) Synthesis, characterization, and electrochemistry of cis-dioxomolybdenum (VI) complexes of Schiff bases derived from carbohydrazide, thiocarbohydrazide, and salicylaldehyde. Crystal structures of [MoO2 (o-OC6H4CH: NN: CSNHN: CHC6H4OH-o) Me2SO] and [(MoO2) 2 (o-OC6H4CH: NN: CONN: CHC6H4O-o)(Me2SO) 2]. cntdot. 0.5 Me2SO. Inorg Chem 29(20):3996–4001

    Article  CAS  Google Scholar 

  • Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3):621–681

    Article  CAS  PubMed  Google Scholar 

  • Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446. doi:10.1158/0008-5472.can-09-1947

    Article  CAS  PubMed  Google Scholar 

  • Darnell G, Richardson D (1999) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: the effect of the ligands on molecular targets involved in proliferation. Blood 94(2):781–792

    CAS  PubMed  Google Scholar 

  • Dragancea D, Arion VB, Shova S, Rentschler E, Gerbeleu NV (2005) Azine-bridged octanuclear copper (II) complexes assembled with a one-stranded ditopic thiocarbohydrazone ligand. Angew Chem Int Ed Engl 44(48):7938–7942

    Article  CAS  PubMed  Google Scholar 

  • Fruehauf JP, Trapp V (2008) Reactive oxygen species: an Achilles’ heel of melanoma? Expert Rev Anticancer Ther 8(11):1751–1757

    Article  CAS  PubMed  Google Scholar 

  • Gao J, Richardson DR (2001) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression. Blood 98(3):842–850

    Article  CAS  PubMed  Google Scholar 

  • Giles GI (2006) The redox regulation of thiol dependent signaling pathways in cancer. Curr Pharm Des 12(34):4427–4443

    Article  CAS  PubMed  Google Scholar 

  • Hauschild A, Eggermont A, Jacobson E, O’Day S (2009) Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM). Paper presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29–June 2, Orlando, Florida

  • Jansson PJ, Sharpe PC, Bernhardt PV, Richardson DR (2010) Novel thiosemicarbazones of the ApT and DpT series and their copper complexes: identification of pronounced redox activity and characterization of their antitumor activity. J Med Chem 53(15):5759–5769

    Article  CAS  PubMed  Google Scholar 

  • Kalinina E, Chernov N, Saprin A (2008) Involvement of thio-, peroxi-, and glutaredoxins in cellular redox-dependent processes. Biochemistry (Mosc) 73(13):1493–1510

    Article  CAS  Google Scholar 

  • Kalinowski DS, Richardson DR (2007) Future of toxicology iron chelators and differing modes of action and toxicity: the changing face of iron chelation therapy. Chem Res Toxicol 20(5):715–720

    Article  CAS  PubMed  Google Scholar 

  • Kalinowski DS, Yu Y, Sharpe PC, Islam M, Liao YT, Lovejoy DB, Richardson DR (2007) Design, synthesis, and characterization of novel iron chelators: structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents. J Med Chem 50(15):3716–3729

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Garcia AMG, Meyskens FL (2012) NADPH oxidase 1 overexpression enhances invasion via matrix metalloproteinase-2 and epithelial–mesenchymal transition in melanoma cells. J Invest Dermatol 132(8):2033–2041

    Article  CAS  PubMed  Google Scholar 

  • Lovejoy DB, Richardson DR (2002) Novel “hybrid” iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells. Blood 100(2):666–676

    Article  CAS  PubMed  Google Scholar 

  • Lovejoy DB, Jansson PJ, Brunk UT, Wong J, Ponka P, Richardson DR (2011) Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes. Cancer Res 71(17):5871–5880

    Article  CAS  PubMed  Google Scholar 

  • Manoj E, Kurup MP, Fun H-K, Punnoose A (2007) Self-assembled macrocyclic molecular squares of Ni (II) derived from carbohydrazones and thiocarbohydrazones: structural and magnetic studies. Polyhedron 26(15):4451–4462

    Article  CAS  Google Scholar 

  • Moubaraki B, Murray KS, Ranford JD, Vittal JJ, Wang X, Xu Y (1999) Preparation, characterisation and structures of copper (II) complexes of an asymmetric anti-cancer drug analogue†. J Chem Soc Dalton Trans 20:3573–3578

    Article  Google Scholar 

  • Nagai M, Vo NH, Ogawa LS, Chimmanamada D, Inoue T, Chu J, Barsoum J (2012) The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radic Biol Med 52(10):2142–2150

    Article  CAS  PubMed  Google Scholar 

  • Noulsri E, Richardson DR, Lerdwana S, Fucharoen S, Yamagishi T, Kalinowski DS, Pattanapanyasat K (2009) Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells. Am J Hematol 84(3):170–176

    Article  CAS  PubMed  Google Scholar 

  • O’Day S, Gonzalez R, Lawson D, Weber R, Hutchins L, Anderson C, Jacobson E (2009) Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J Clin Oncol 27(32):5452–5458

    Article  PubMed  Google Scholar 

  • Peethambaram P, Burton J, Oberg A, Gomez-Dahl L, Isham C, Tibodeau J, Erlichman C (2007) A phase 2 trial of flavopiridol and cisplatin in platinum-resistant ovarian cancer. Mol Cancer Ther 6(11 Supplement):A140

    Google Scholar 

  • Richardson DR, Sharpe PC, Lovejoy DB, Senaratne D, Kalinowski DS, Islam M, Bernhardt PV (2006) Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity. J Med Chem 49(22):6510–6521

    Article  CAS  PubMed  Google Scholar 

  • Sander C, Hamm F, Elsner P, Thiele J (2003) Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol 148(5):913–922

    Article  CAS  PubMed  Google Scholar 

  • Sathisha MP, Revankar VK, Pai KSR (2007) Synthesis, structure, electrochemistry, and spectral characterization of bis-isatin thiocarbohydrazone metal complexes and their antitumor activity against ehrlich ascites carcinoma in swiss albino mice. Met-Based Drugs 2008:362105. doi:10.1155/2008/362105

    PubMed Central  Google Scholar 

  • Shah MA, Schwartz GK (2001) Cell cycle-mediated drug resistance an emerging concept in cancer therapy. Clin Cancer Res 7(8):2168–2181

    CAS  PubMed  Google Scholar 

  • Siriwardana G, Seligman PA (2015) Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells. Physiol Rep 3(3):e12341

    Article  PubMed  PubMed Central  Google Scholar 

  • Tas F (2012) Metastatic behavior in melanoma: timing, pattern, survival, and influencing factors. J Oncol 2012:9. doi:10.1155/2012/647684

    Article  Google Scholar 

  • Tew KD, Townsend DM (2011) Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol 15(1):156–161. doi:10.1016/j.cbpa.2010.10.016

    Article  CAS  PubMed  Google Scholar 

  • Venza M, Visalli M, Beninati C, De Gaetano GV, Teti D, Venza I (2015) Cellular mechanisms of oxidative stress and action in melanoma. Oxid Med Cell Longev 2015:11. doi:10.1155/2015/481782

    Article  Google Scholar 

  • Whitnall M, Howard J, Ponka P, Richardson DR (2006) A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Nat Acad Sci 103(40):14901–14906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaura M, Mitsushita J, Furuta S, Kiniwa Y, Ashida A, Goto Y, Takata M (2009) NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression. Cancer Res 69(6):2647–2654

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Kalinowski DS, Kovacevic Z, Siafakas AR, Jansson PJ, Stefani C, Richardson DR (2009) Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors. J Med Chem 52(17):5271–5294

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

F Akladios acknowledges the receipt of an Australian Postgraduate Award (APA). CJP wishes to thank the CSU Pharmacy Foundation for a grant partially funding this study. CJP and SDA thank the Kolling Institute (Royal North Shore Hospital) for the donation and characterization of the MelRm cell line employed in this study. We thank Dr N Proschogo (U Sydney) for the provision of mass spectrometry services and Professor D Richardson for discussions relating to the activation of copper and other metals.

Author information

Authors and Affiliations

  1. School of Biomedical Sciences, Charles Sturt University, Orange, NSW, 2800, Australia

    Fady N. Akladios, Scott D. Andrew & Christopher J. Parkinson

Authors
  1. Fady N. Akladios
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott D. Andrew
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Parkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher J. Parkinson.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akladios, F.N., Andrew, S.D. & Parkinson, C.J. Investigation of the cytotoxic implications of metal chelators against melanoma and approaches to improve the cytotoxicity profiles of metal coordinating agents. Biometals 29, 789–805 (2016). https://doi.org/10.1007/s10534-016-9945-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-016-9945-1

Keywords

Search

Navigation