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

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 = PPh3 2 Titanocref and PEt3 4 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR3)] (PR3 = PPh3 1 cref; PEt3 3 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.

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs

“…An intriguing approach to exploit the distinct cytotoxic mechanism of action of Ti(IV) and Au(I) is synergizing their activity in the form of heterometallic compounds [115][116][117][118][119][120][121][122]. These compounds build off of the titanocene structure.…”

New Organometallic Ruthenium(II) Compounds Synergistically Show Cytotoxic, Antimetastatic and Antiangiogenic Activities for the Treatment of Metastatic Cancer

“…Unexpectedly, NAMI‐A yielded less antimetastatic activity than Ru8 , suppressing the gap closure with 19.0 % at 32 μ m , which was comparable with the activity of Ru8 at 4 μ m (Figure 4 B). To eliminate the influence of cytotoxicity, the wound‐healing assay was further performed at low drug concentrations (e.g., IC 10 and IC 20 , Table S4) [31] . Encouragingly, Ru8 remained active against migration as compared to untreated cells.…”

“…To eliminate the influence of cytotoxicity,the wound-healing assayw as further performed at low drug concentrations (e.g.,I C 10 and IC 20 ,T able S4). [31] En- couragingly, Ru8 remained active against migration as compared to untreated cells. However, at the concentrations of IC 10 or IC 20 ,N AMI-A failed to inhibit the gap closure in the cells (Figure S30).…”

Heterometallic Multinuclear Complexes as Anti‐Cancer Agents‐An Overview of Recent Developments

“…The incorporation of the PEt 3 auxiliary ligand was motivated by the activity observed for the Au‐PEt 3 fragment of Auranofin. Extensive in vitro studies revealed that both 98 and 104 (Figure ), inhibit cell migration, proliferation and angiogenesis, as well as the inhibition of TrxR and VEGF (vascular endothelial growth factor) …”