Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer

Benelita T Elie; Jacob Fernández-Gallardo; Natalia Curado; Mike A Cornejo; Joe W Ramos; María Contel

doi:10.1016/j.ejmech.2018.10.034

Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer

Eur J Med Chem. 2019 Jan 1:161:310-322. doi: 10.1016/j.ejmech.2018.10.034. Epub 2018 Oct 17.

Authors

Benelita T Elie¹, Jacob Fernández-Gallardo², Natalia Curado², Mike A Cornejo², Joe W Ramos³, María Contel⁴

Affiliations

¹ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Biology PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA.
² Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA.
³ Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, USA.
⁴ Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, NY, 11210, USA; Biology PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA; Chemistry PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA; Biochemistry PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY, 10016, USA; Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, USA. Electronic address: MariaContel@brooklyn.cuny.edu.

Abstract

Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene-gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(η-C₅H₅)₂TiMe(μ-mba)Au(PEt₃)] (4) Titanofin. The compound is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)] (PR₃ = PPh₃2 Titanocref and PEt₃4 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR₃)] (PR₃ = PPh₃1 cref; PEt₃3 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers associated with these processes such as prometastatic IL(s), MMP(s), TNF-α, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overexpressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1α whose overexpression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer.

Keywords: Angiogenesis; Bimetallic; Mechanisms; Metastasis; Renal cancer; Titanium-gold.

MeSH terms

Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / pathology
Molecular Conformation
Neovascularization, Pathologic / drug therapy*
Neovascularization, Pathologic / pathology
Organometallic Compounds / chemistry
Organometallic Compounds / pharmacology*
Phosphines / chemistry
Phosphines / pharmacology*
Structure-Activity Relationship

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Coordination Complexes
Organometallic Compounds
Phosphines
titanocene
phosphine

Abstract

MeSH terms

Substances

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