A heterometallic ruthenium–gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer

Abstract

Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium–gold (Ru–Au) family of compounds based on Au–N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au–NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru–Au–NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer.

Graphical Abstract

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Abbreviations

ANCE-1:

[AuCl(IMes)]

ATCC:

American Type Culture Collection

ADAM:

A disintegrin and metalloproteinase

Auranofin:

[(2R,3R,4S,5R,6S)-3,4,5-Tris(acetyloxy)-6-{[(triethyl-λ5-phosphanylidene)aurio]sulfanyl}oxan-2-yl]methyl acetate

Caki-1:

Human clear cell renal cell carcinoma

Cisplatin:

Cis-diamminedichloroplatinum(II)

dppm:

Diphenylphosphanylmethyl(diphenyl)phosphane 

DTNB:

3,3′-Disulfanediylbis(6-nitrobenzoic acid)

HCT 116:

Human colorectal carcinoma

HUVEC:

Human umbilical vein endothelial cells

ILs:

Interleukins

IMes:

1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene

IRM90:

Human foetal lung fibroblast

MMPs:

Matrix metalloproteinase

NHC:

N-Heterocyclic carbene

p-cymene:

4-Isopropyltoluene

R:

[Ru(p-Cymene)Cl2(dppm-κP)]

RANCE-1:

[Cl2(p-Cymene)Ru(μ-dppm)Au(IMes)]ClO4

TNB2− :

5-Thio-2-nitrobenzoic acid

TrRx:

Thioredoxin reductase

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We thank the National Cancer Institute (NCI) for grant 1SC1CA182844 (M.C.) and Dr. Karen Hubbard for providing infrastructure and advice. We are grateful to Dr. Natalia Curado and Yu-Fung Mui for their assistance in the preparation of the metallic compounds, Mike A. Cornejo for his assistance with some IC50 assays, and Ciara Bagnall for her technical expertise in imaging and immunocytochemistry.

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Correspondence to María Contel.

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Elie, B.T., Pechenyy, Y., Uddin, F. et al. A heterometallic ruthenium–gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer. J Biol Inorg Chem 23, 399–411 (2018). https://doi.org/10.1007/s00775-018-1546-8

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Keywords

  • Bimetallic
  • Ruthenium–gold
  • Renal cancer
  • Mechanisms
  • Auranofin