Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

Abstract

Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs.

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…243 In 2021, Pozza et al reported two different piperidine dithiocarbamic acid (Pipe-DTC) Au( iii ) complexes. Complex 338 exhibited significant activity against HCT116 and AGS (adenocarcinoma gastric cell line) cells with IC 50 values of 1.1 ± 0.7 μM and 0.4 ± 0.2 μM, respectively 244 (Fig. 29).…”

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer

“…However, not all metals are equivalent. For instance, we recently showed that ruthenium and gold complexes with similar ligands did not trigger the same molecular mechanisms, which is well illustrated by [AuCl 2 (pipeDTC)] and β-[Ru 2 (pipeDTC) 5 ]Cl [ 43 ] ( Figure 7 B). The first compound was able to induce the DNA damage response factor p53 and the autophagy protein p62.…”

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…289,290 There are reports on functionalized crown ether-DTC compounds capable to bind and cleave DNA. [291][292][293] Research within this field has focused on compounds that inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis. [294][295][296] In work done on crown ethers coupled with dithiocarbamate, a diazacrown ether moiety was used as a linker, which could also act as an ionophore, in the synthesis of binuclear metal complexes.…”

“…There are reports on functionalized crown ether-DTC compounds capable to bind and cleave DNA. 291–293 Research within this field has focused on compounds that inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis. 294–296…”