Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

Yeo, Chien Ing; Ooi, Kah Kooi; Tiekink, Edward R. T.

doi:10.3390/molecules23061410

Cited by 147 publications

(98 citation statements)

References 194 publications

(261 reference statements)

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“…The results of recent studies pointed toward the induction of apoptosis as a major cytotoxic mechanism of gold(III) complexes against cancer cells [22,28]. Apoptosis is mediated by two main pathways, an extrinsic pathway that involve cell surface receptors, and an intrinsic pathway via mitochondria and the endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

et al. 2021

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Background / Aim. We investigated cytotoxicity of Au(III) complexes with pincer type ligands against cervical carcinoma cells (HeLa), breast cancer cells (MDA-MB-231 and 4T1) and colon carcinoma cells (HCT116 and CT26). We also examined the type and mechanism of cell death that these complexes induced in cancer cells. Methods.Cytotoxicity of Au(III) complexes was investigated by MTT assay. Apoptosis of treated cancer cells was measured by flow cytometry and applying Annexin V/7AAD staining. The expressions of active proapoptotic protein Bax, antiapoptotic protein Bcl-2 and the percentage of cells containing cleaved caspase-3 in treated cancer cells was determined by flow cytometry. Results. Complex 1 showed the most potent anti-tumor effect on HeLa cells, both compared to other two examined gold complexes and compared to cisplatin. The IC50 values on HeLa cells after 72 hours were 1.3 ± 0.4 μM, 3.4 ± 1.3 μM, 5.7 ± 0.6 μM, 26.7 ± 6.5 μM for complexes 1, 2, 3 and cisplatin, respectively. Complex 1 also exhibited highest cytotoxicity against MDA-MB-231 and HCT116 cells compared to other tested compounds. The results of Annexin V/7AAD staining showed that all three complexes induced apoptosis in treated cells. Our gold(III) complexes induced apoptosis by caspasedependent mechanism, but we did not observe that an activation of the internal pathway of apoptosis occurred in treated cancer cells. Conclusion. According to the results of our in vitro study, all three compounds and especially complex 1 are promising candidates for a new generation of anticancer drugs. Uvod. Ispitivali smo citotoksičnost Au(III) kompleksa sa ligandima tipa pincer protiv ćelija karcinoma grlića materice (HeLa), ćelija raka dojke (MDA-MB-231 i 4T1) i ćelija karcinoma kolona (HCT116 i CT26). TakoĎe smo ispitali tip i mehanizam ćelijske smrti koji su ovi kompleksi indukovani u ćelijama raka. Metode. Citotoksičnost Au(III) kompleksa je ispitivana pomoću MTT testa. Apoptoza tretiranih ćelija raka je merena protočnom citometrijom i primenom bojenja Aneksin V/7AAD. Ekspresija aktivnog proapoptotičnog proteina Bax, antiapoptotskog proteina Bcl-2 i procenat ćelija koje sadrže aktivnu kaspazu-3 u tretiranim ćelijama raka je odreĎena protočnom citometrijom. Rezultati. Kompleks 1 je pokazao najsnažniji antitumorski efekat na HeLa ćelije, kako u 4 poreĎenju sa drugim ispitivanim kompleksima zlata, tako i u poreĎenju sa cisplatinom.Vrednosti IC50 kompleksa zlata na HeLa ćelije nakon 72 sata bile su 1,3 ± 0,4 μM, 3,4 ± 1,3 μM, 5,7 ± 0,6 μM, 26,7 ± 6,5 μM za komplekse 1, 2, 3 i cisplatin. Kompleks 1 je takoĎe pokazao najvišu citotoksičnost prema MDA-MB-231 i HCT116 ćelijama u poreĎenju sa drugim testiranim jedinjenjima. Rezultati bojenja aneksinomV/7AAD pokazali su da sva tri kompleksa indukuju apoptozu u tretiranim ćelijama. Naši kompleksi zlata(III) indukovali su apoptozu mehanizmom koji je zavisio od kaspaze, ali nismo pokazali da je u tretiranim ćelijama raka došlo do aktivacije unutrašnjeg puta apoptoze. Zakljuĉak. Prema rezultatima naše in vitro studij...

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Section: Discussionmentioning

confidence: 99%

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

et al. 2021

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“…The antiproliferative activity against different tumor cell lines was shown by gold(I) complexes obtained from the reaction of [Au(SPyCOOH)(PR3)] complex (SPyCOOH = nicotinic acid thiolate) by the functionalization of its carboxylic group with different amino acids, ester or amide derivatives of these amino acids or with peptide moieties [20,21]. Gold(I) complexes 7-24 of the general formula [Au(SPyCOR)(PPh3)], in which R = methyl ester of amino acid (7)(8)(9)(10)(11)(12), amino acid (13)(14)(15)(16)(17)(18) and amide derivative of the corresponding amino acid (19)(20)(21)(22)(23)(24) have been structurally modified. This modification was performed by changing the type of phosphine ligand in [Au(SPyCOR)(PPh3)] complex (PPh2Py instead of PPh3; complex 25) and the nature of the coupled amino acid (R) including its structural modification or peptide functionalization (26)(27)(28)(29)(30)(31)(32) and increasing the number of Au(I) ions per complex unit (33) (Figure 2a and b) [21].…”

Section: Gold(i) Complexes Containing Amino Acids and Peptides Moietiesmentioning

confidence: 99%

“…Following the medicinal relevance of gold complexes for the treatment of rheumatoid arthritis, research has continued to uncover the potential of gold complexes as agents for the treatment of cancer [4][5][6][7][8][9][10][11][12][13], and various bacterial and fungal infections and tropical diseases, such as malaria, trypanosomiasis and leishmaniasis [14,15]. In some cases, gold complexes were found to be more active than the clinically used agents, e.g., cisplatin for the cancer treatment [5].…”

Section: Introductionmentioning

confidence: 99%

“…Different classes of ligands have been used for the synthesis of biologically active gold complexes, including phosphines, N-heterocyclic carbenes, thiolates, polyamines, pyridine, bipyridine, terpyridine, phenanthroline, and their derivatives, macrocyclic ligands (cyclam), porphyrins and dithiocarbamates [4][5][6][7][8][9][10][11][12][13][14][15]. Besides them, amino acids and peptides represent two important classes of ligands which are also important as building blocks of proteins and enzymes and show a wide range of biological activities [16].…”

Section: Introductionmentioning

confidence: 99%

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Amino Acids and Peptides as Versatile Ligands in the Synthesis of Antiproliferative Gold Complexes

2020

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Gold complexes have been traditionally employed in medicine, and currently, some gold(I) complexes, such as auranofin, are clinically used in the treatment of rheumatoid arthritis. In the last decades, both gold(I) and gold(III) complexes with different types of ligands have gained considerable attention as potential antitumor agents, showing superior activity both in vitro and in vivo to some of the clinically used agents. The present review article summarizes the results achieved in the field of synthesis and evaluation of gold complexes with amino acids and peptides moieties for their cytotoxicity. The first section provides an overview of the gold(I) complexes with amino acids and peptides, which have shown antiproliferative activity, while the second part is focused on the activity of gold(III) complexes with these ligands. A systematic summary of the results achieved in the field of gold(I/III) complexes with amino acids and peptides could contribute to the future development of metal complexes with these biocompatible ligands as promising antitumor agents.

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“…Gold thiolate compounds are potent inhibitors of TrxR acting in the nanomolar range (reviewed in Scalcon et al and Yeo et al). Auranofin (Figure ) is an orally available, lipophilic, organogold thiolate compound [(2,3,4,6‐tetra‐ O ‐acetyl‐1‐thio‐β‐ d ‐glucopyranosato‐κ)(triethylphosphoranylidene)gold], approved for rheumatoid arthritis treatment, with anti‐inflammatory and potential antineoplastic activities.…”

Section: Repurposing Drugs As Potent Pro‐oxidative Anticancer Agentsmentioning

confidence: 99%

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Ralph

Nozuhur

ALHulais

et al. 2019

Medicinal Research Reviews

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Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

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Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?

Cited by 147 publications

References 194 publications

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

New gold pincer-type complexes induce caspase-dependent apoptosis in human cancer cells in vitro

Amino Acids and Peptides as Versatile Ligands in the Synthesis of Antiproliferative Gold Complexes

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

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