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.

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