Arene ruthenium(ii) complex, a potent inhibitor against proliferation, migration and invasion of breast cancer cells, reduces stress fibers, focal adhesions and invadopodia

Abstract

Effective chemotherapy drugs for cancer that would inhibit tumor growth and suppress metastasis are currently lacking. In this study, a series of arene ruthenium complexes, [(η6-arene)Ru(H2iip)Cl]Cl (arene = p-cymene, RAWQ03; CH3C6H5, RAWQ04; and C6H6, RAWQ11), were synthesized and their inhibitory activity against tumor cells were evaluated. The results showed that the complex RAWQ11 inhibited the growth of MDA-MB-231 breast cancer cells by inducing S-phase arrest, which is closely related to the inhibition of cell mitosis-mediated cell nucleus damage. Further studies showed that RAWQ11 can inhibit the invasion and metastasis of MDA-MB-231 cells. The morphology of MDA-MB-231 cells changed, the number of focal adhesions decreased, and the stress fibers de-polymerized upon dealing with the complex RAWQ11. The FITC-gelatin assay confirmed that the formation of invadopodia in MDA-MB-231 cells was significantly blocked by RAWQ11. Furthermore, RAWQ11 can block the AKT signal pathway by upregulating the PTEN expression through binding and downregulating miR-21. These results demonstrated that this type of arene ruthenium(ii) complex can block the invadopodia formation by regulating the PTEN/AKT signal pathway mediated by miR-21 to inhibit the invasion and metastasis of breast cancer cells. Therefore, this complex can be used as a potential dual functional agent to inhibit the growth and metastasis of tumor cells.

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).…”

Pyrithione-based ruthenium complexes as inhibitors of aldo–keto reductase 1C enzymes and anticancer agents

“…14 Moreover, pyrithione zinc is remarkably effective towards acute myeloid leukemia by triggering apoptosis through NF-κB inhibition, 15 and towards cervical tumor cells by activating p53 and its dependent genes resulting in loss of membrane potential and activation of apoptosis. [22][23][24][25] Beside conventional chemotherapy, ruthenium-based coordination compounds are studied in conjunction with electrotherapy (i.e. 20,21 Several other compounds are in the preclinical phases of investigations.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[76] Another class of ruthenium(II)-arene complexes that have gained interest are termed rutheniumarene complexes 1,2ethylenediamine (RAED) complexes, but unlike RAPTA compounds, they preferentially bind to DNA, [18,79] whereas RAPTA-C prefers to bind to the highly electronegative cleft region on the surface of the histone proteins in nucleosome core particles making up chromatin. [80] This binding preference is in stark contrast to platinum-based drugs. [81] A representative example of a "more sophisticated" RAPTA compound is RAPTA-EA ( Figure 1), which combines the basic RAPTA unit covalently linked to ethacrynic acid, a glutathione S-transferase (GST) inhibitor.…”