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

  • Benelita T. Elie
  • Yuriy Pechenyy
  • Fathema Uddin
  • María ContelEmail author
Original Paper


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


Bimetallic Ruthenium–gold Renal cancer Mechanisms Auranofin 





American Type Culture Collection


A disintegrin and metalloproteinase


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


Human clear cell renal cell carcinoma






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

HCT 116

Human colorectal carcinoma


Human umbilical vein endothelial cells






Human foetal lung fibroblast


Matrix metalloproteinase


N-Heterocyclic carbene








5-Thio-2-nitrobenzoic acid


Thioredoxin reductase


Vascular endothelial growth factor



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.


  1. 1.
    Pelletier F, Comte V, Massard A, Wenzel M, Toulot S, Richard P, Picquet M, Le Gendre P, Zava O, Edafe F, Casini A, Dyson PJ (2010) J Med Chem 53:6923–6933CrossRefPubMedGoogle Scholar
  2. 2.
    Liu Y, Chen TF, Wong Y-S, Mei W-J, Huang X-M, Yang F, Liu J, Zheng W-J (2010) Chem-Biol Interact 183:349–356CrossRefPubMedGoogle Scholar
  3. 3.
    Wenzel M, Bertrand B, Eymin M-J, Comte V, Harvey JA, Richard P, Groessl M, Zava O, Amrouche H, Harvey PD, Le Gendre P, Picquet M, Casini A (2011) Inorg Chem 50:9472–9480CrossRefPubMedGoogle Scholar
  4. 4.
    Bjelosevic H, Guzei IA, Spencer LC, Persson T, Kriel FH, Hewer R, Nell MJ, Gut J, van Resburg CEJ, Rosenthal P, Coates J, Darkwa J, Elmroth SKC (2102) J Organomet Chem 720:52–59CrossRefGoogle Scholar
  5. 5.
    Kaushik NK, Mishra A, Ali A, Adhikari JS, Verma AK, Gupta R (2012) J Inorg Biol Chem 17:1217–1230CrossRefGoogle Scholar
  6. 6.
    Nieto D, Gonzalez-Vadillo AM, Bruna S, Pastor CJ, Rios-Luci C, Leon LG, Padron JM, Navarro-Ranninger C, Cuadrado I (2012) Dalton Trans 41:432–441CrossRefPubMedGoogle Scholar
  7. 7.
    Lease N, Vasileviski V, Carreira M, de Almeida A, Sanaú M, Hirva P, Casini A, Contel M (2013) J Med Chem 56:5806–5818CrossRefPubMedGoogle Scholar
  8. 8.
    Garcia-Moreno E, Gascon S, Rodriguez-Yoldi MJ, Cerrada E, Laguna M (2013) Organometallics 32:3710–3720CrossRefGoogle Scholar
  9. 9.
    Barreiro E, Casas JS, Couce MD, Sanchez A, Sordo J, Vazquez-Lopez EM (2104) J Inorg Biochem 131:68–75CrossRefGoogle Scholar
  10. 10.
    Wenzel M, Bigaeva E, Richard P, Le Gendre P, Picquet M, Casini A, Bodio E (2014) J Inorg Biochem 141:10–16CrossRefPubMedGoogle Scholar
  11. 11.
    Fernandez-Moreira V, Marzo I, Gimeno C (2014) Chem Sci 5:4434–4446CrossRefGoogle Scholar
  12. 12.
    Zaidi Y, Arjmand F, Zaidi N, Usmani JA, Zubair H, Akhatar K, Hossain M, Shadab GGHA (2014) Metallomics 6:1469–1479CrossRefPubMedGoogle Scholar
  13. 13.
    Govender P, Lemmerhirt H, Hutton AT, Therrien B, Bednarski PJ, Smith GS (2014) Organometallics 33:5535–5545CrossRefGoogle Scholar
  14. 14.
    Bertrand B, Citta A, Franken IL, Picquet M, Folda A, Scalcon V, Rigobello MP, Le Gendre P, Casini A, Bodio E (2015) J Biol Inorg Chem 20:1005–1020CrossRefPubMedGoogle Scholar
  15. 15.
    Boselli L, Carraz M, Mazeres S, Paloque L, Gonzalez G, Benoit-Vical F, Valentin A, Hemmert C, Gornitzka H (2015) Organometallics 34:1046–1055CrossRefGoogle Scholar
  16. 16.
    Nieto D, Bruna S, Gonzalez-Vadillo AM, Perles J, Carrillo-Hermosilla F, Antiniolo A, Padron JM, Plata GB, Cuadrado I (2015) Organometallics 34:5407–5417CrossRefGoogle Scholar
  17. 17.
    Nithyakumar A, Alexander V (2015) Dalton Trans 44:17800–17809CrossRefPubMedGoogle Scholar
  18. 18.
    Fenton JB, Busse M, Rendina LM (2015) Aus J Chem 68:576–580CrossRefGoogle Scholar
  19. 19.
    Ma L, Ma R, Wang Z, Yiu S-M, Zhu G (2016) Chem Commun 52:10735–10738CrossRefGoogle Scholar
  20. 20.
    Singh N, Jang S, Jo J-H, Kim DH, Park DW, Kim I, Kim H, Kang SC, Chi K-W (2016) Chemistry-A Eur J 22:16157–16164CrossRefGoogle Scholar
  21. 21.
    Lopes J, Alves D, Morais TS, Costa PJ, Piedade M, Fatima M, Marques F, Villa de Brito MJ, Garcia MH (2017) J Inorg Biochem 169:68–78CrossRefPubMedGoogle Scholar
  22. 22.
    Luengo A, Fernandez-Moreira V, Marzo I, Gimeno MC (2017) Inorg Chem 56:15159–15170CrossRefPubMedGoogle Scholar
  23. 23.
    González-Pantoja JF, Stern M, Jarzecki AA, Royo E, Robles-Escajeda E, Varela-Ramirez A, Aguilera RJ, Contel M (2011) Inorg Chem 50:11099–11110CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fernández-Gallardo J, Elie BT, Sulzmaier F, Sanaú M, Ramos JW, Contel M (2014) Organometallics 33:6669–6681CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fernández-Gallardo J, Elie BT, Sadhukha T, Prabha S, Sanaú M, Rotenberg SA, Ramos JW, Contel M (2015) Chem Sci 6: 5269-5283. (b) Contel M, Fernández-Gallardo J, Elie BT, Ramos JW. US Patent 9,315,531 (04/19/2016)Google Scholar
  26. 26.
    Mui YF, Fernández-Gallardo J, Gubran A, Elie BT, Maluenda I, Sanaú M, Navarro O, Contel M (2016) Organometallics 35:1218–1227CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Massai L, Fernández-Gallardo J, Guerri A, Arcangeli A, Pillozzi S, Contel M, Messori L (2015) Dalton Trans 44:11067–11076CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fernández-Gallardo J, Elie BT, Sanaú M, Contel M (2016) Chem Commun 52:3155–3158CrossRefGoogle Scholar
  29. 29.
    Dean TC, Yang M, Liu M, Grayson JM, DeMartino AW, Day CS, Lee J, Furdui CM, Bierbach U (2017) ACS Med Chem Lett 8:572–576CrossRefPubMedGoogle Scholar
  30. 30.
    Das S, Sinha S, Britto R, Somasundaram K, Samuelson AG (2010) J Inorg Biochem 104:93–104CrossRefPubMedGoogle Scholar
  31. 31.
    Fremont P, Scott NM, Stevens ED, Nolan SP (2005) Organometallics 24:2411–2418CrossRefGoogle Scholar
  32. 32.
    Varghese E, Busselberg D (2014) Cancers 6:2243–2258 and refs therein CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Roder C, Thomson MJ (2015) Drugs R D 15:13–20CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Adhireksan Z, Davey GE, Campomanes P, Groessl M, Clavel CM, Yu H, Nazarov AA, Yeo CHF, Ang WH, Droge P, Rothlisberger U, Dyson PJ, Davey CA (2014) Nature Comm 5:3462CrossRefGoogle Scholar
  35. 35.
    Nakayaa A, Sagawa M, Muto A, Uchida H, Ikedaa Y, Kizari M (2011) Leukemia Res 35:243–249CrossRefGoogle Scholar
  36. 36.
    Liu C, Liu Z, Li M, Li X, Wong Y-S, Ngai S-M, Zheng W, Zhang Y, Chen T (2013) PLoS ONE 8:e53945CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fan C, Zheng W, Fu X, Li X, Wong Y-S, Chen T (2014) Cell Death and Disease 5:e191Google Scholar
  38. 38.
    Park S-H, Lee JH, Berek JS, Hu MC-T (2014) Int J Oncol 45:1691–1698CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Denkert C, Furstenberg A, Daniel PT, Koch I, Kobell M, Weichert W, Siegert A, Hauptmann S (2013) Oncogene 22:8653–8661CrossRefGoogle Scholar
  40. 40.
    Moutasim KA, Nystrom ML, Thomas GJ (2011) Methods Mol Biol 731:333–343CrossRefPubMedGoogle Scholar
  41. 41.
    Hulkower KI, Herber RL (2011) Pharmaceutics 3:107–124CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    DeCicco-Skinner KL, Henry GH, Cataisson C, Tabib T, Gwilliam JC, Watson NJ, Bullwinkle EM, Falkenburg L, O’Neill RC, Morin A, Wiest JS (2014) J Vis Exp 91:e51312Google Scholar
  43. 43.
    Cheng X, Holenya P, Can S, Alborzinia H, Rubbiani R, Ott I, Wölfl S (2014) Mol Cancer 13:221CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Farina AR, Tacconelli A, Cappabianca L, Masciulli MP, Holmgren A, Beckett GJ, Gulino A, Mackay AR (2001) Eur J Biochem 268:405–413CrossRefPubMedGoogle Scholar
  45. 45.
    Lim HV, Hong S, Jin W, Lim S, Kim SJ, Kang HJ, Park EH, Ahn K, Lim CJ (2005) Exp Mol Med 37:497–506CrossRefPubMedGoogle Scholar
  46. 46.
    Marzano C, Gandin V, Folda A, Scutari G, Bindoli A, Rigobello AP (2007) Free Radic Biol Med 42:872–881CrossRefPubMedGoogle Scholar
  47. 47.
    Zou M, Zhang X, Xu C (2016) Cell Oncol 39:47–57CrossRefGoogle Scholar
  48. 48.
    Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, Hsieh CY (2003) Oncogene 22:1517–1527CrossRefPubMedGoogle Scholar
  49. 49.
    Suzuki M, Tetsuka T, Yoshida S, Watanabe N, Kobayashi M, Matsui N, Okamoto T (2000) FEBS Lett 465:23–27CrossRefPubMedGoogle Scholar
  50. 50.
    Quail DF, Joyce JA (2013) Nat Med 19:1423–1437CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kwong W-L, Lam K-Y, Lok C-N, Lai Y-T, Lee P-Y, Che C-M (2016) Angew Chem Int Ed 55:13524–13528CrossRefGoogle Scholar
  52. 52.
    Lippitz BE, Harris RA (2016) Oncoimmunology 11(5):e1093722CrossRefGoogle Scholar
  53. 53.
    Welte T, Zhang XH (2015) Mediators Inflamm 2015:804347.
  54. 54.
    Kim N-M, Lee M-Y, Park S-J, Choi J-S, Oh M-K (2007) Kim In-S. Immunology 122:607–614CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Li Q, Chen B, Cai J, Sun Y, Wang G, Li Y, Li R, Feng Y, Han B, Li J, Tian Y, Yi L, Jiang C (2016) PLoS ONE 11:e0151815CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Overall CM, Kleifeld O (2006) Nat Rev Cancer 6:227–239CrossRefPubMedGoogle Scholar
  57. 57.
    He ZH, Chen N, Wang D, Bin Y, She JX (2014) Eur J Pharmacol 740:240–247CrossRefPubMedGoogle Scholar
  58. 58.
    Woo JH, Lim JH, Kim YH, Suh SI, Min DS, Chang JS, Lee YH, Park JW, Kwon TK (2004) Oncogene 23:1845–1853CrossRefPubMedGoogle Scholar
  59. 59.
    Woessner JF, Nagase H (2000) Matrix metalloproteinases and TIMPs: protein profile. Oxford University Press, OxfordGoogle Scholar
  60. 60.
    Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D (2008) Biochimie 90:369–379CrossRefPubMedGoogle Scholar
  61. 61.
    Schlomann U, Koller G, Conrad C, Ferdous T, Golfi P, Garcia AM, Höfling S, Parsons M, Costa P, Soper R, Bossard M, Hagemann T, Roshani R, Sewald N, Ketchem RR, Moss ML, Rasmussen FH, Miller MA, Lauffenburger DA, Tuveson DA, Nimsky C, Bartsch JW (2015) Nat Commun 6:6175CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yousef EM, Tahir MR, St-Pierre Y, Gaboury LA (2014) BMC Cancer 14:609CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Olson OC, Joyce JA (2015) Nat Rev Cancer 15:712–729CrossRefPubMedGoogle Scholar
  64. 64.
    Sevenich L, Joyce JA (2014) Genes Dev 28:2331–2347CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Bakst RL, Xiong H, Chen CH, Deborde S, Lyubchik A, Zhou Y, He S, McNamara W, Lee SY, Olson OC, Leiner IM, Marcadis AR, Keith JW, Al-Ahmadie HA, Katabi N, Gil Z, Vakiani E, Joyce JA, Pamer E, Wong RJ (2017) Cancer Res 22:6400–6414CrossRefGoogle Scholar
  66. 66.
    Casini A, Gabbiani C, Sorrentino F, Rigobello MP, Bindoli A, Geldbach TJ, Marrone A, Re N, Hartinger CG, Dyson PJ, Messori L (2008) J Med Chem 51:6773–6781CrossRefPubMedGoogle Scholar

Copyright information

© SBIC 2018

Authors and Affiliations

  • Benelita T. Elie
    • 1
    • 2
    • 4
  • Yuriy Pechenyy
    • 4
  • Fathema Uddin
    • 4
  • María Contel
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Chemistry, Brooklyn CollegeThe City University of New YorkBrooklynUSA
  2. 2.Biology PhD Program, The Graduate CenterThe City University of New YorkNew YorkUSA
  3. 3.Chemistry PhD Program, The Graduate CenterThe City University of New YorkNew YorkUSA
  4. 4.Biology Department, The City College of New YorkCity University of New YorkNew YorkUSA

Personalised recommendations