Nucleus-enriched Ruthenium Polypyridine Complex Acts as a Potent Inhibitor to Suppress Triple-negative Breast Cancer Metastasis In vivo

Abstract

Polypyridine Ru(II) complexes have long been deemed to excellent antitumor agents that inhibit the proliferation of breast cancer cells. Nevertheless, their effects on the metastatic potency of breast cancer cells need further research. Herein, a class of polypyridine Ru(II) complexes coordinated with phenazine derivates (DPPZ) ([Ru(bpy)2(DPPZ-R)](ClO4)2, Ru(bpy)2DPPZ: R = -H, Ru(bpy)2BrDPPZ: R = -Br, Ru(bpy)2MDPPZ: R = -CH3, Ru(bpy)2BnDPPZ: R = −acene, Ru(bpy)2BEDPPZ: R = -C ≡ C(C6H5)) was synthesized by introducing different substituent groups to regulate the electron cloud density and planarity of the main ligands. Results indicated that this class of DPPZ-based Ru(II) complexes exhibited promising inhibitory effect against MDA-MB-231 triple-negative breast cancer cells, especially for Ru(bpy)2BEDPPZ, which is comparable with that of cisplatin. In addition, Ru(bpy)2BEDPPZ effectively inhibited the migration and invasion of MDA-MB-231 cells in vitro and suppressed focal adhesion and stress fiber formation. Moreover, it effectively blocked MDA-MB-231 cell metastasis in blood vessels and restrained angiogenesis formation in a zebrafish xenograft breast cancer model. Further studies showed that the mechanisms may involve DNA damage-mediated apoptosis probably due to Ru(bpy)2BEDPPZ, which was enriched in the cell nucleus and induced DNA damage. All these results suggested that the DPPZ-based Ru(II) complexes can act as potent anti-metastasis agents.

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

“…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).…”

“…[51] The induction of G2/M arrest is typical of RAPTA-C, [50] NAMI-A, [52] treatment and has also been observed in other ruthenium-based compounds. [45,53] This arrest 2 for both cell lines. The data reported in the graph and standard deviation of the sample mean result from at least two independent trials.…”

Rationally Designed Ruthenium Complexes for Breast Cancer Therapy

“…Finally, Mei et al (2019) reported a class of ruthenium(II) phenazine derivatives (DPPZ) with interesting anticancer properties against TNBC cells [136]. The most promising results were obtained for compound (34) (Figure 10), which displayed a notable inhibitory activity against the proliferation (IC 50 = 17.2 ± 0.9 µM), migration, and invasion of MDA-MB-231 cells.…”

“…Furthermore, an in vivo anticancer evaluation of (34) in the xenograft model of human MDA-MB-231 in zebrafish showed that the number of cancer cells was notably reduced compared with the control group, suggesting that (34) can effectively inhibit the proliferation of TNBC cells in zebrafish. Moreover, a scarce number of MDA-MB-231 cells were found in the blood vessels of zebrafish, suggesting that (34) might inhibit the metastasis of the cancer cells in vivo [136].…”

Inhibition of Matrix Metalloproteinases and Cancer Cell Detachment by Ru(II) Polypyridyl Complexes Containing 4,7-Diphenyl-1,10-phenanthroline Ligands—New Candidates for Antimetastatic Agents

“…Ruthenium polypyridyl complexes have been tested for many years for their use in anticancer therapy as cytotoxic agents [10][11][12]. Recently, ours and other studies have shown that ruthenium polypyridyl compounds in addition to their well-documented cytotoxic activity can affect various cell properties such as detachment, motility, invasion, colonization ability, and others that are crucial for metastasis formation and development [13][14][15][16][17][18][19]. The detailed mechanism of such activity is still largely unknown; however, some of these compounds have been shown to strongly alter cell adhesion properties.…”