In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R4Show more
In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R4 position of the phenyl ring of the 2H-indazole chelating ligand are present. The cytotoxicity of Ru(II) and Ir(III) complexes has been evaluated against different human cancer cell lines (HeLa, MCF-7, and A549) in a concentration-dependent manner. The new iridium complex with isopropyl substituent in the phenyl ring of the 2H-indazole moiety showed good cytotoxic activity against MCF-7 cells with an IC50 value 3.5 μM. The complex also exhibited cytotoxicity comparable to that of cisplatin. The ability of this compound inducing apoptosis was tested by nuclear condensation, cell membrane blebbing and caspase 3/7 activation. Further, this iridium complex is capable of inhibiting cancer cell migration when tested in MCF-7 cell line. Subsequently, we have studied the DNA binding and protein binding ability of the newly synthesized iridium complex. Show less
💬 Evidence (1 matches)
apoptosis: «...The new iridium complex 5b with isopropyl substituent in the phenyl ring of 2H-indazole moiety showed good activity against MCF-7 cells and show apoptosis with increased caspase-3/7 activity....»
This report presents the first known p-cymene ruthenium quinaldamide complexes which are stabilised by a hydrogen-bridging atom, [{(p-cym)Ru(II)X(N,N)}{H(+)}{(N,N)XRu(II)(p-cym)}][PF6] (N,N = function Show more
This report presents the first known p-cymene ruthenium quinaldamide complexes which are stabilised by a hydrogen-bridging atom, [{(p-cym)Ru(II)X(N,N)}{H(+)}{(N,N)XRu(II)(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(μ-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 ⇔ NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H(+), which are counter-balanced by a PF6 counterion. X-ray crystallographic analysis is presented for six new structures with OO distances of 2.420(4)-2.448(15) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index >1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis. Show less
💬 Evidence (5 matches)
apoptosis: «...Apoptotic analyses revealed a clear correlation between chemosensitivity and levels of apoptosis, whereby the most active compound induces the highest percentage of apoptosis....»
apoptosis: «...Compound 2 is the least active ... show the least amount of apoptotic cells. (From Induction of Cancer Cell Death by Apoptosis section)...»
apoptosis: «...The 2’,4’-difluoro compounds 3 and 6, which were the most active compounds in the MTT chemosensitivity studies, also induced significant levels of apoptotic cell death against HCT116 cancer cell lines...»
apoptosis: «...The 2’,4’-difluoro compounds 3 and 6... also induced significant levels of apoptotic cell death... compound 6 which was the most active against the MTT assay showed significant apoptosis, with 84% apo...»
apoptosis: «...the more active compound 5 induces apoptosis at a concentration of 20 µM and gave 35% apoptotic cells....»
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1HShow more
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 μM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis. Show less
💬 Evidence (1 matches)
apoptosis: «...The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis....»
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii Show more
Human acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia. The fusion of PML and RARα genes is responsible for over 98% of cases of APL. In this work, we found that a Ru(ii) arene complex, [(η6-p-bip)Ru(en)Cl][PF6] (Ru-1), can selectively react with PML, leading to zinc-release and protein unfolding. Consequently, the degradation of the fusion protein PML-RARα occurs, which causes the differentiation of APL cells. In addition, Ru-1 can also bind to DNA and trigger apoptosis of APL cells. Therefore, Ru-1 acts as a dual functional agent that inhibits the growth of APL cells and induces cell differentiation. In contrast, the other non-selective Ru(ii) compound, though also highly reactive to PML, does not exhibit anti-APL activity. The selectivity of Ru-1 to PML suggests a new strategy for the development of anti-APL drugs using ruthenium agents. Show less
💬 Evidence (1 matches)
apoptosis: «...To verify the cell apoptosis resulting from the DNA binding of Ru-1, the expression of apoptotic pathway proteins, including caspase-3, cleaved caspase-3, PARP-1 and cleaved PARP-1, was measured... Th...»
A new series of half-sandwich ruthenium(II) compounds [(η6-arene)Ru(L)Cl][CF3SO3] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); ar Show more
A new series of half-sandwich ruthenium(II) compounds [(η6-arene)Ru(L)Cl][CF3SO3] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); arene = p-cymene, L = L2 (2); arene = benzene, L = L1 (3); arene = benzene, L2 (4); L1 = 2-[1-(p-tolyl)-1H-1,2,3-triazol-4-yl]pyridine and L2 = 1,1'-di-p-tolyl-1H,1'H-4,4'-bi(1,2,3-triazole) have been synthesized and fully characterized by 1H and 13C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 1, 2, and 4 have been determined by single-crystal X-ray diffraction. The cytotoxic activity of 1-4 was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds 2 and 4 showed no cytotoxic activity toward tumor cell lines, compounds 1 and 3 were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC50 concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC50 concentrations of compound 1 or 3 led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound 3 displayed low levels of angiogenesis induction, compound 1 showed an ability to induce cell cycle delay and to interfere with cell migration. When the in vivo toxicity studies using zebrafish and chicken embryos are considered, compounds 1 and 3, which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both in vitro and in vivo. Show less
💬 Evidence (3 matches)
apoptosis: «...compounds 1 and 3 induced apoptosis in approximately 17% and 37% of A2780 cells....»
autophagy: «...compound 1 can induce autophagic death in 80% of A2780 cells...»
autophagy: «...exposure to compound 3 led to an induction of autophagy in only 40% of the cells...»
Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1 Show more
Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meim = 1-methylimidazole, dppb = 1,4-Bis(diphenylphosphino)butane, bpy = 2,2'-bipyridine, 4,4'-DMbpy = 4,4'-dimethyl-2,2'-bipyridine, 5,5'-DMbpy = 5,5'-dimethyl-2,2'-bipyridine and phen = 1,10-phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF6 (5) and [RuCl(1Meim)(dppb)(5,5'-DMbpy)]PF6 methanol solvate (6) where PF6 = hexafluorophosphate, showing one 1-methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, 1H, 13C{1H} and 31P{1H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1-4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer. Show less
💬 Evidence (1 matches)
apoptosis: «...Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation....»
Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (< Show more
Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3) and [Ru(mpca)(bipy)(dppb)]PF6 (4) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment. Show less
💬 Evidence (1 matches)
apoptosis: «...coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death t...»
apoptosis: «...Mechanistic studies revealed that all complexes caused apoptosis induction by activating caspases with upregulation of Bax and downregulation of Bcl-2....»
Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor dru Show more
Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. Show less
💬 Evidence (1 matches)
apoptosis: «...Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive...»
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respon Show more
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respond to hormonal therapy, and they develop resistance to chemotherapeutic drugs. On the other hand, the severe side effects of cisplatin represent an obstacle for its clinical use. Ruthenium (Ru)-based complexes have emerged as promising antitumor and antimetastatic substitutes for cisplatin. In this study, we demonstrated the effects of a Ru/biphosphine complex, containing gallic acid (GA) as a ligand, [Ru(GA)(dppe)2]PF6, hereafter called Ru(GA), on a TNBC cell line, and compared them to the effects in a nontumor breast cell line. Ru(GA) complex presented selective cytotoxicity against TNBC over nontumor cells, inhibited its migration and invasion, and induced apoptosis. These effects were associated with the increased amount of transferrin receptors (TfR) on tumor cells, compared to nontumor ones. Silencing of TfR decreased Ru(GA) effects on TNBC cells, demonstrating that these receptors were at least partially responsible for Ru(GA) delivery into tumor cells. The Ru(GA) compound must be further studied in different in vivo assays in order to investigate its antitumor properties and its toxicity in complex biological systems. Show less
💬 Evidence (1 matches)
apoptosis: «...Ru(GA) complex presented selective cytotoxicity against TNBC over nontumor cells, inhibited its migration and invasion, and induced apoptosis....»
Three novel Ru(II) complexes, namely, (RuCl2[La][DMSO]2)·H2O (Ru1), (RuCl2[Lb][DMSO]2) (Ru2), and (RuCl2 Show more
Three novel Ru(II) complexes, namely, (RuCl2[La][DMSO]2)·H2O (Ru1), (RuCl2[Lb][DMSO]2) (Ru2), and (RuCl2[Lc][DMSO]2) (Ru3), which respectively contain 3-(2'-benzimidazolyl)coumarin (La), 3-(2'-benzimidazolyl)-7-fluoro-coumarin (Lb), and 3-(2'-benzimidazolyl)-7-methoxyl-coumarin (Lc), were first designed and characterized. Ru2 showed potent antitumor activity against NCI-H460 cells (IC50 = 0.30 ± 0.02 μM) and high selectivity between NCI-H460 cancer cells and normal HL-7702 cells. Ru2 induced NCI-H460 apoptosis via telomerase inhibition, which involved DNA damage, cell-cycle distribution, and S phase-protein down-regulation. However, Ru1 did not demonstrate such effects in NCI-H460 cells, which is undoubtedly associated with the key regulatory role of the 7-fluoro substituted group in the Lb ligand of Ru2. Ru2 exhibited considerably higher anticancer efficacy (inhibition rate [IR] = 61.3%) compared with cisplatin (IR= 25.5%) in a NCI-H460 xenograft mouse model. Thus, this coumarin Ru(II) compound is a promising Ru2-targeting telomerase anticancer agent. Show less
💬 Evidence (2 matches)
apoptosis: «...Ru1 (15.78 μM, ca. 18.9%) induced the apoptosis...»
apoptosis: «...Ru2 induced NCI-H460 apoptosis via telomerase inhibition, which involved DNA damage, cell-cycle distribution, and S phase-protein down-regulation. Ru2 (0.30 μM, ca. 88.4%) induced the apoptosis ... in...»
Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remai Show more
Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)](2+) (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)](2+) before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing. Show less
💬 Evidence (1 matches)
autophagy: «...quantifying LC3 levels revealed a distinct increase in the ratio of LC3-II to LC3-I, a hallmark of autophagy induction, in 2-treated cells from exposure times of 8h onwards...»
In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the Show more
In the present study, it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells. Apart from the induction of apoptosis, it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-regulation of LC3-II. Furthermore, scavenging of reactive oxygen species (ROS) by antioxidant NAC or Tiron inhibited the release of cytochrome c, caspase-3 activity, and eventually rescued cancer cells from Ru1-mediated apoptosis, suggesting that Ru1 inducing apoptosis was partially caspase 3-dependent by triggering ROS-mediated mitochondrial dysfunction in A549 and NCI-H460 cells. Further study indicated that the extracellular signal-regulated kinase (ERK) signaling pathway was involved in Ru1-induced autophagy in A549 and NCI-H460 cells. Moreover, blocking autophagy using pharmacological inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhanced Ru1-induced apoptosis, indicating the cytoprotective role of autophagy in Ru1-treated A549 and NCI-H460 cells. Finally, the in vivo mice bearing A549 xenografts, Ru1 dosed at 10 or 20 mg/kg significantly inhibited tumor growth. Show less
💬 Evidence (2 matches)
apoptosis: «...it was found that the ruthenium (II) imidazole complex [Ru(Im)4(dppz)]2+ (Ru1) could induce significant growth inhibition and apoptosis in A549 and NCI-H460 cells....»
autophagy: «...it was reported for the first time that Ru1 induced an autophagic response in A549 and NCI-H460 cells as evidenced by the formation of autophagosomes, acidic vesicular organelles (AVOs), and the up-re...»
Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel Show more
Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway. Show less
💬 Evidence (1 matches)
apoptosis: «...Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitocho...»
Here, we examine the photophysical properties of five ruthenium(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and functionalized bipyridine (R₁bpy-R₂, where R₁= H or CH3, Show more
Here, we examine the photophysical properties of five ruthenium(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and functionalized bipyridine (R₁bpy-R₂, where R₁= H or CH3, R₂= H, CH₃, COO⁻,4-[3-(2-nitro-1H-imidazol-1-yl)propyl] or 1,3-dicyclohexyl-1-carbonyl-urea) towards development of luminescence probes for cellular imaging. These complexes have been shown to interact with albumin and the formed adducts exhibited up to eightfold increase in the luminescence quantum yield as well as the average lifetime of emission. It was demonstrated that they cannot bind to DNA through the intercalation mode and its luminescence in the presence of DNA is quenching. Cell viability experiments indicated that all complexes possess significant dose-dependent cytotoxicity (with IC₅₀ 5-19 μM) on 4T1 breast cancer cell line and their anti-proliferative activity correlates very well with their lipophilicity. Cellular uptake was studied by measuring the ruthenium content in cells using ICP-MS technique. As expected, the better uptake is directly related to higher lipophilicity of doubly charged ruthenium complexes while uptake of monocationic one is much lower in spite of the highest lipophilicity. Additionally staining properties were assessed using flow cytometry and fluorescence microscopy. These experiments showed that complex with 1,3-dicyclohexyl-1-carbonyl-urea substituent exhibits the best staining properties in spite of the lowest luminescence quantum yield in buffered solution (pH 7.4). Our results point out that both the imaging and cytotoxic properties of the studied ruthenium complexes are strongly influence by the level of internalization and protein interaction. Show less
💬 Evidence (1 matches)
apoptosis: «...4T1 cells after incubation with ruthenium compounds show marked morphological sign of apoptosis, such as decreasing amount of detached cells, cells rounding and shrinkage... The results suggest that c...»
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic c Show more
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer. Show less
💬 Evidence (1 matches)
apoptosis: «...We observed that RANCE-1 (1) induce apoptosis in 82% of cells killed and Auranofin (86%) of cells (Figure 1)....»
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In th Show more
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)2dppz](ClO4)2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer. Show less
💬 Evidence (1 matches)
apoptosis: «...In addition, 75.9% of cells were apoptotic following exposure to Lipo-Ru for 12 h, while less than 5% displayed signs of apoptosis in Ru-treated cells and control cells ( Figure 5b and 5d ). To furthe...»
A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and n Show more
A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed. Show less
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apoptosis: «...As reflected by the number of subdiploid cells (Figure 4 and Table 4), a moderate effect on apoptosis induction was observed at the 50 μM dose....»
apoptosis: «...the exposure of MDA-MB-231 cells to 10, 20, and 40 μM 3 for 24 h triggered a significant increase in the number of cells under S-phase arrest and in the induction of cell apoptosis....»
Cisplatin was the first metal-based therapeutic agent approved for the treatment of human cancers, but its clinical activity is greatly limited by tumor drug resistance. This work utilized the parent Show more
Cisplatin was the first metal-based therapeutic agent approved for the treatment of human cancers, but its clinical activity is greatly limited by tumor drug resistance. This work utilized the parent complex [Ru(phen)2(PIP)](2+) (1) to develop three Ru(II) complexes (2-4) with different positional modifications. These compounds exhibited similar or superior cytotoxicities compared to cisplatin in HeLa, A549 and multidrug-resistant (A549R) tumor cell lines. Complex 4, the most potent member of the series, was highly active against A549R cancer cells (IC50 = 0.8 μM). This complex exhibited 178-fold better activity than cisplatin (IC50 = 142.5 μM) in A549R cells. 3D multicellular A549R tumor spheroids were also used to confirm the high proliferative and cytotoxic activity of complex 4. Complex 4 had the greatest cellular uptake and had a tendency to accumulate in the mitochondria of A549R cells. Further mechanistic studies showed that complex 4 induced A549R cell apoptosis via inhibition of thioredoxin reductase (TrxR), elevated intracellular ROS levels, mitochondrial dysfunction and cell cycle arrest, making it an outstanding candidate for overcoming cisplatin resistance. Show less
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apoptosis: «...A double-staining Annexin V/PI apoptosis kit and flow cytometry were used to investigate the nature of A549R cell death induced by complex 4. The results are shown in Fig. 7b. At a concentration as lo...»
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal Show more
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity. Show less
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apoptosis: «...ROS generation leads to oxidative stress and can trigger apoptosis. In order to confirm if apoptosis is the mechanism of cell death caused by the compounds under study, apoptosis induction was studied...»
Herein, we report the synthesis and characterization of a bishomoleptic and a trisheteroleptic ruthenium (II) polypyridyl complex, namely, [Ru(bpy)2(2, 2'-pq)](PF6)2 (1) and [Ru(bpy) (phen) (2, 2'-pq) Show more
Herein, we report the synthesis and characterization of a bishomoleptic and a trisheteroleptic ruthenium (II) polypyridyl complex, namely, [Ru(bpy)2(2, 2'-pq)](PF6)2 (1) and [Ru(bpy) (phen) (2, 2'-pq)](PF6)2 (2), respectively, where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and 2, 2'-pq = 2-(2'-pyridyl)-quinoxaline. The complexes were characterized by elemental analysis, TGA, 1H-NMR, FT-IR, UV-Vis, emission spectroscopy, and electrochemistry. Their structures were confirmed by single-crystal X-ray diffraction analysis. Complexes 1 and 2 were crystalized in orthorhombic, Pbca, and monoclinic, P21/n systems, respectively. Various spectroscopic techniques were employed to investigate the interaction of both complexes with calf thymus DNA (CT-DNA). The experimental data were confirmed by molecular docking studies, employing two different DNA sequences. Both complexes, 1 and 2, bind with DNA via a minor groove mode of binding. MTT experiments revealed that both complexes induce apoptosis of MCF-7 (breast cancer) cells in low concentrations. Confocal microscopy indicated that 2 localizes in the nucleus and internalizes more efficiently in MCF-7 than in HEK-293. Show less
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apoptosis: «...MTT experiments revealed that both complexes induce apoptosis of MCF-7 (breast cancer) cells in low concentrations....»
Title: Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product.
Abstract: Show more
Title: Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product.
Abstract: A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)-p-cymene moiety to obtain an organoruthenated complex containing the natural product (Ru(pip)). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods (MSNRs), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid (PL) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles (PL-Ru(pip)@MSNRs), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles. Show less
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apoptosis: «...While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells....»
Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms.
Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] Show more
Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms.
Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. Show less
💬 Evidence (1 matches)
apoptosis: «...induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase casca...»
apoptosis: «...The cell death mechanism of the active complexes 2 and 3 was found to be apoptosis as assessed by flow cytometry and staining methods....»
apoptosis: «...The results obtained from AO/EB staining assay indicate that the complex and nanoformulation induce both apoptotic and necrotic mode of cell death, but mainly through apoptosis....»
Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compou Show more
Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy. Show less
💬 Evidence (4 matches)
apoptosis: «...leading to a combined cell death mechanism via apoptosis and autophagy (abstract). Also: '60 ± 6% of apoptotic cells for complex 2' (Results section)....»
apoptosis: «...leading to a combined cell death mechanism via apoptosis and autophagy (abstract). Also: 'an increase of apoptotic markers was observed, such as chromatin condensation and apoptotic bodies, correspond...»
autophagy: «...leading to a combined cell death mechanism via apoptosis and autophagy (abstract). Also: '70 ± 4% of autophagic cells for complex 2' (Results section)....»
autophagy: «...leading to a combined cell death mechanism via apoptosis and autophagy (abstract). Also: 'Cells exposed to complexes 1 and 2 showed an accumulation of autophagolysosomes characteristic of the inductio...»
Title: Asymmetrically Coordinated Heterodimetallic Ir-Ru System: Synthesis, Computational, and Anticancer Aspects.
Abstract: Herein, we present an unprecedented formation of a heterodinuclear complex Show more
Title: Asymmetrically Coordinated Heterodimetallic Ir-Ru System: Synthesis, Computational, and Anticancer Aspects.
Abstract: Herein, we present an unprecedented formation of a heterodinuclear complex [{(ppy)2IrIII}(μ-phpy){RuII(tpy)}](ClO4)2 {[1](ClO4)2} using terpyridyl/phenylpyridine as ancillary ligands and asymmetric phpy as a bridging ligand. The asymmetric binding mode (N∧N-∩-N∧N∧C-) of the phpy ligand in {[1](ClO4)2} is confirmed by 1H, 13C, 1H-1H correlated spectroscopy (COSY), high-resolution mass spectrum (HRMS), single-crystal X-ray crystallography techniques, and solution conductivity measurements. Theoretical investigation suggests that the highest occupied molecular orbital (HOMO) and the least unoccupied molecular orbital (LUMO) of [1]2+ are located on iridium/ppy and phpy, respectively. The complex displays a broad low energy charge transfer (CT) band within 450-575 nm. The time-dependent density functional theory (TDDFT) analysis suggests this as a mixture of metal-to-ligand charge transfer (MLCT) and ligand-to-ligand charge transfer (LLCT), where both ruthenium, iridium, and ligands are involved. Complex {[1](ClO4)2} exhibits RuIIIrIII/RuIIIIrIII- and RuIIIIrIII/RuIIIIrIV-based oxidative couples at 0.83 and 1.39 V, respectively. The complex shows anticancer activity and selectivity toward human breast cancer cells (IC50; MCF-7: 9.3 ± 1.2 μM, and MDA-MB-231: 8.6 ± 1.2 μM) over normal breast cells (MCF 10A: IC50 ≈ 21 ± 1.3 μM). The Western blot analysis and fluorescence microscopy images suggest that combined apoptosis and autophagy are responsible for cancer cell death. Show less
💬 Evidence (2 matches)
apoptosis: «...The Western blot analysis and fluorescence microscopy images suggest that combined apoptosis and autophagy are responsible for cancer cell death....»
autophagy: «...The Western blot analysis and fluorescence microscopy images suggest that combined apoptosis and autophagy are responsible for cancer cell death....»
Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epi Show more
Triple negative breast cancer (TNBC) is a heterogeneous subtype of breast tumors that does not exhibit the expression of estrogen and progesterone receptors, neither the amplification of the human epidermal growth factor receptor 2 (HER-2) gene. Despite all the advances in cancer treatments, the development of new anticancer drugs for TNBC tumors is still a challenge. There is an increasing interest in new agents to be used in cancer treatment. Ruthenium is a metal that has unique characteristics and important in vivo and in vitro results achieved for cancer treatment. Thus, in this work, with the aim to develop anticancer drugs, three new ruthenium complexes containing acylthiourea ligands have been synthesized and characterized: trans-[Ru(PPh3)2(N,N-dibutyl-N'-benzoylthioureato-k2O,S)(2,2'-bipyridine (bipy))]PF6(1), trans-[Ru(PPh3)2(N,N-dimethyl-N'-thiophenylthioureato-k2O,S)(bipy)]PF6(2) and trans-[Ru(PPh3)2(N,N-dimethyl-N'-benzoylthioureato-k2O,S)(bipy)]PF6(3). Then, the cytotoxicity of these three new ruthenium complexes was investigated in TNBC MDA-MB-231 and in non-tumor MCF-10A cells. Complex (2) was the most selective complex and was chosen for further studies to verify its effects on cell morphology, adhesion, migration, invasion, induction of apoptosis and DNA damage in vitro, as well as its toxicity and capacity of causing DNA damage in vivo. Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells at lower concentrations compared to non-tumor MCF-10A cells, suggesting an effective action for this complex on tumor cells. Finally, complex (2) did not induce toxicity or caused DNA damage in vivo when low doses were administered to mice. Show less
💬 Evidence (1 matches)
apoptosis: «...Complex (2) inhibited proliferation, migration, invasion, adhesion, changed morphology and induced apoptosis, DNA damage and nuclear fragmentation of TNBC cells ... Complex (2) was able to induce apop...»
A slow hydrolyzing imidazole-based Ru(II)-arene complex [(L)Ru(II)(η(6)-p-cym)(Cl)](PF6) (1) with excellent stability in the extracellular chloride concentration shows better activity under hypoxia an Show more
A slow hydrolyzing imidazole-based Ru(II)-arene complex [(L)Ru(II)(η(6)-p-cym)(Cl)](PF6) (1) with excellent stability in the extracellular chloride concentration shows better activity under hypoxia and strong resistance to glutathione (GSH) in vitro under hypoxic conditions. 1 arrests the cell cycle in sub G1 and G2/M phases and leads to apoptosis. Show less
💬 Evidence (1 matches)
apoptosis: «...1 arrests the cell cycle in sub G1 and G2/M phases and leads to apoptosis. The ladder assay of 1 against MCF-7 cells shows that the DNA is cleaved to form nucleosome-sized fragments ... confirming tha...»