In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake

Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142, New Zealand.
Journal of Inorganic Biochemistry (Impact Factor: 3.44). 03/2008; 102(2):303-10. DOI: 10.1016/j.jinorgbio.2007.09.003
Source: PubMed


In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an example of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.

5 Reads
  • Source
    • "Ag(I) complexes (Berners-Price and Sadler 1988; Liu et al. 2008; Santini et al. 2011). The effect of the various ligands on the viability of the MCF-7 cells was studied in order to determine, by comparison , whether they showed any cytotoxic activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is much interest currently in the design of metal compounds as drugs and various metal compounds are already in clinical use. These include gold(I) compounds such as auranofin and the anti-cancer platinum(II) complex, cisplatin. Bis-chelated gold(I) phosphine complexes have also shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity. In this study, silver(I) thiocyanate compounds linked to four specific ligands, were synthesized and characterized. These silver-phosphine adducts included [AgSCN{P(4-MeC6H4)3}2]2 (1); [AgSCN{P(4-ClC6H4)3}2]2 (2); [AgSCN{P(4-MeOC6H4)3}2]2 (3); [AgSCN(PPh3)2]2 (4). The compounds were found to be toxic to MCF-7 breast cancer cells while the ligands on their own were not toxic. Our findings further indicate that the silver(I) phosphine compounds induce apoptotic cell death in these breast cancer cells. In addition, the compounds were not toxic to nonmalignant fibroblast cells at the IC50 concentrations. This is an indication that the compounds show selectivity towards the cancer cells.
    Biology of Metals 06/2015; 28(4). DOI:10.1007/s10534-015-9865-5 · 2.50 Impact Factor
  • Source
    • ", have been shown to possess antitumor activity in cisplatin-resistant CH-1 human ovarian carcinoma cells (McKeage et al. 2000). In another study, lipophilic Ag(I) and Au(I) bidentate pyridyl phosphine complexes were able to decrease the viability of ovarian cancer cells to ±50 % after a 96-hour treatment (Liu et al. 2008). These authors also studied the effect of the phosphine ligands on their own. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Esophageal cancer is one of the least studied cancers and is found to be prominent in black South African males. It is mainly diagnosed in the late stages, and patients tend to have a low 5-year survival rate of only 10 %. Silver is generally used as an antimicrobial agent, with limited reports on anticancer studies. In this study, dimeric silver(I) thiocyanate complexes were used containing a variation of 4-substitued triphenylphosphines, including [AgSCN(PPh3)2]2 (1), [AgSCN{P(4-MeC6H4)3}2]2 (2), [AgSCN{P(4-FC6H4)3}2]2 (3) and [AgSCN{P(4-ClC6H4)3}2]2 (4). All four complexes, with their respective phosphine ligands, PPh3 (L1), P(4-MeC6H4)3 (L2), P(4-FC6H4)3 (L3) and P(4-ClC6H4)3 (L4), were subjected to in vitro toxicity studies in SNO-esophageal cancer cells, using an alamarBlue® assay. Morphological changes, including blebbing and apoptotic body formation, were observed. Phosphatidylserine externalization, a marker of apoptosis, was quantified by flow cytometry. The phosphine ligands L1–L4, on their own, had minimal effect on the malignant while complexes 1–4 resulted in significant cell death. A 10× decreased concentration of these complexes had similar effects than cisplatin, used as the positive control. These complexes show promise as anticancer agents.
    BioMetals 12/2014; 28(1). DOI:10.1007/s10534-014-9817-5 · 2.50 Impact Factor
  • Source
    • "Following euthanasia of animals with intraperitoneal injection of pentobarbitone (90 mg/kg body weight, Chemstock Animal Health, Christchurch, New Zealand), lumbar DRG tissues were dissected and homogenized using a Dounce homogenizer (Glas-Col, Terre Haute, IN, USA) for 3 min in a lysis buffer containing 250 mM sucrose, 1 mM EDTA, 1 mM EGTA, 0.5% NP-40, 0.1% SDS, and a protease inhibitor mixture (Complete Mini Protease Inhibitor Cocktail tablets; Roche Diagnostics, Indianapolis, IN, USA). The homogenate was centrifuged for 15 min at 500 ×g at 4°C to remove nuclei and large particulate matter, and the protein concentration of the resulting supernatant was determined by a bicinchoninic acid (BCA) assay as previously reported [58]. Protein samples (40 μg) were heated at 95°C for 30 min, resolved in 8% SDS-PAGE, and then transferred to a nitrocellulose membrane (Amersham Pharmacia, Tokyo, Japan) using a Transblot SD apparatus (Bio-Rad, Hercules, CA, USA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks. In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals. In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non-overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin.
    Molecular Pain 09/2010; 6(1):53. DOI:10.1186/1744-8069-6-53 · 3.65 Impact Factor
Show more