Ruthenium Polypyridyl Complexes That Induce Mitochondria-Mediated Apoptosis in Cancer Cells
Department of Chemistry, Jinan University, Guangzhou 510632, People's Republic of China. Inorganic Chemistry
(Impact Factor: 4.76).
07/2010; 49(14):6366-8. DOI: 10.1021/ic100277w
The limitations of cisplatin-based chemotherapy, including high toxicity, undesirable side effects, and drug resistance, have motivated extensive investigations into alternative metal-based cancer therapies. Ruthenium (Ru) possesses several favorable properties suited to rational anticancer drug design and biological applications. In the present study, we synthesized a series of ruthenium polypyridyl complexes containing N,N-chelating ligands, examined their anticancer activities, and elucidated the molecular mechanisms through which they caused the cancer cell death. The results demonstrated that [Ru(phen)(2)-p-MOPIP](PF(6))(2).2H(2)O (RuPOP), a complex with potent antiproliferative activity, is able to induce mitochondria-mediated and caspase-dependent apoptosis in human cancer cells. On the basis of these results, we suggest that RuPOP may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially for melanoma.
Available from: Adisorn Ratanaphan
- "Several ruthenium compounds have exhibited high cytotoxicity towards cancer cells and for inducing apoptosis
[15-17]. In addition, extensive investigations of ruthenium-based compounds has mainly focused on the characterization of ruthenium-DNA adducts
[12,18-20] and has paid less attention to other potential cellular targets. "
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ABSTRACT: Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine.
Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination.
HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity.
This study has revealed the ability of ruthenium complexes to inhibit cell proliferation, induce cell cycle progression and apoptosis. Ruthenium treatment upregulated the marker genes involved in apoptosis and cell cycle progression while it downregulated BRCA1 mRNA and replication of HCC1937 cells. Our results could provide an alternative approach to finding effective therapeutic ruthenium-based agents with promising anticancer activity, and demonstrated that the BRCA1 RING domain protein was a promising therapeutic target for breast cancers.
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ABSTRACT: Three ruthenium(II) polypyridyl complexes [Ru(dmb)2(dadppz)]2+1, [Ru(bpy)2(dadppz)]2+2 and [Ru(phen)2(dadppz)]2+3 were synthesized and characterized by elemental analysis, ES-MS, 1H NMR and 13C NMR. Their DNA-binding behaviors were investigated by absorption titration, fluorescence spectroscopy and viscosity measurements. Cytotoxicity in vitro, apoptosis, cell cycle arrest, cellular uptake and reactive oxygen species assays were performed. The complexes were found to show moderate DNA-binding affinities and high cytotoxicities toward A549, BEL-7402, MG-63 and SKBR-3 cell lines. These complexes can effectively induce apoptosis of BEL-7402. In cell cycle assays, the complexes induced S-phase arrest on BEL-7402 cells and G0/G1-phase arrest on SKBR-3 cells. The DNA-binding experiments showed that the three complexes interact with CT-DNA through an intercalative mode.
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ABSTRACT: Two new ruthenium(II) polypyridyl complexes, [Ru(bpy)2(DMDPPZ)](ClO4)2 (1) (bpy = 2,2′-bipyridine, DMDPPZ = 3,6-dimethyldipyrido[3,2-a:2′,3′-c]phenazine) and [Ru(dmb)2(DMDPPZ)](ClO4)2 (2) (dmb = 4,4′-dimethyl-2,2′-bipyridine), have been synthesized and their DNA-binding, photoinduced DNA cleavage, and cell cytotoxicity are studied. The complexes show good binding to calf thymus DNA in the order: 1 > 2. Both complexes exhibit efficient DNA cleavage upon irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The cytotoxic activity of 1 and 2 was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method. These complexes effectively inhibit the proliferation of tumor cells. The antioxidant activity against hydroxyl radical (•OH) was also explored.
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