Effects of the ruthenium-based drug NAMI-A on the roles played by TGF-β1 in the metastatic process

Abstract

The ruthenium-based drug NAMI-A, characterised by its selectivity against solid tumour metastases, promotes TGF-β1-dependent fibrosis and the reduction of the release of MMPs in the primary tumour. The aim of the study was to examine the interaction of NAMI-A with TGF-β1 in the process of metastasis formation. NAMI-A (1) affects the secretion of TGF-β1 in metastatic MDA-MB-231 cells rather than in non-tumorigenic HBL-100 cells, (2) prevails over TGF-β1 with regard to the invasive capacity of the treated cells, and (3) contrasts integrin-dependent migration stimulated by TGF-β1. It, thus, appears that the effects of NAMI-A on cell invasion and migration are best summarised as an interference with TGF-β1 and a reduction of its activity in these events. At a molecular level, the similar activity of NAMI-A and TGF-β1 on RhoA GTPase supports its interaction with cell surface integrins while TGF-β1 can activate it by interaction with its TGFβR receptor. The inhibition of TGF-β1-induced migration of MDA-MB-231 cells by NAMI-A cannot simply be attributed to a modulation of the Smad2 and p38MAPK pathways. In conclusion, the effects of NAMI-A on the biological role of TGF-β1 in cancer metastasis are insufficient to attribute the responsibility for the anti-metastatic activity of the ruthenium-based drug to this target alone.

Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)‐Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells

“…It is known that sometimes the toxicity in vitro does not correlate with what happens in mice xenograft models. The values found for NAMI‐A and RAPTA‐C were as expected as these compounds are known to have very high IC 50 values in MDA‐MB‐231 and they do not display cytotoxic properties [43,44] …”

“…The values found for NAMI-A and RAPTA-C were as expected as these compounds are known to have very high IC 50 values in MDA-MB-231 and they do not display cytotoxic properties. [43,44] Ruthenium compounds are known for their variation in intracellular interactions, showing localization to nuclear, [45] lysosomal, [46] and mitochondrial [47] compartments, amongst others. To understand the potential target of Ru-IM (1) ruthenium distribution between cytosolic and mitochondrial fractions after 2 and 24 h treatments with 2 μM of compound were analyzed with inductively coupled plasma optical emission spectrometry (ICP-OES) in TNBC MDA-MB-231 and non-malignant breast MCF10a lines (Figure 1).…”

Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity

“…While the mechanism of action of RAPTA-C still remains to be fully elucidated, it has been suggested that the formation of adducts in chromatin histone proteins are involved 18 . This mechanism is different to that observed for the ruthenium(III) compounds mentioned above 19 20 21 . We have also demonstrated the effect of RAPTA-C on the suppression of primary tumor growth in preclinical studies 22 .…”

Metallodrugs: an approach against invasion and metastasis in cancer treatment

“…Furthermore, these complexes have shown some selectivity and the ability to overcome the resistance faced by platinum-based therapeutic agents. NAMI-A is selective for metastatic cancer cells and acts through the TGF-b pathway [50]. KP1019, also known as FFC14A, induces significant upregulation of 284 genes and downregulation of 76 genes, some of which are associated with cell cycle arrest through ROS, mitogen-activated protein (MAP) kinases [51], and chromatin assembly.…”