Inhibitory Effects of the Ruthenium Complex KP1019 in Models of Mammary Cancer Cell Migration and Invasion

Abstract

The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second ruthenium compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role.

Three-dimensional and co-culture models for preclinical evaluation of metal-based anticancer drugs

“…Another possible explanation for increased cytotoxicity in vivo is albumin-mediated uptake [54,55]. Previous studies regarding the anti-invasive activity of rutheniumbased compounds revealed certain anti-invasive activity of [38]. Our results, however, could not demonstrate anti-invasive activity of KP1339, neither in the transwell nor in the spheroid-based assays.…”

“…4b). While a related compound investigated previously [38] caused significant reduction of cell migration and invasion in breast cancer cell lines, the ruthenium complex KP1339 had no anti-invasive activity in the models applied here. KP1537 and oxaliplatin, with significant activity in the transwell assay, were inactive in the spheroid invasion assay.…”

Microwave-assisted synthesis of polypyridyl ruthenium(ii) complexes as potential tumor-targeting inhibitors against the migration and invasion of Hela cells through G2/M phase arrest

“…[21][22][23][24] A number of Ru complexes have been designed and their anti-metastasis activities against various tumours have been investigated extensively. [25][26][27] For example, NAMI-A 28,29 and KP1019 30 have entered phase II clinical studies as NAMI-A can selectively reduce tumour metastasis and inhibit tumour cell invasion in vitro and KP1019 can inhibit the migration and invasion of MDA-MB-231 breast cancer cells by reducing the release of the extracellular matrix (MMP-2/9). In addition, the Ru complex RM175 also exhibits tumour metastasis inhibition and reduces the invasion and metastasis by promoting cell-cell readhesion and by decreasing the release of metalloproteinases (MMPs).…”

Bis‐picolinamide Ruthenium(III) Dihalide Complexes: Dichloride‐to‐Diiodide Exchange Generates Single trans Isomers with High Potency and Cancer Cell Selectivity

“…However, there has been a lack of suitable trans ruthenium derivatives due to the propensity of the molecules to undergo isomerisation. The first reported cytotoxic trans ‐ruthenium complexes were KP1019 ( g ) and NAMI‐A ( h ),– which in Phase I clinical trials were well tolerated showing only limited side‐effects . NAMI‐A has also undergone Phase II clinical studies in combination with gemcitabine, however, this combination had some adverse toxicity and failed to show any improvement in results compared with gemcitabine treatment alone .…”