A2780 Human Ovarian Cancer Cell Research Articles

C-Geranylated flavanone diplacone enhances in vitro antiproliferative and anti-inflammatory effects in its copper(II) complexes

Two copper(II) complexes containing diplacone (H4dipl), a naturally occurring C-geranylated flavanone derivative, in combination with bathophenanthroline (bphen) or 1,10-phenanthroline (phen) with the composition [Cu3(bphen)3(Hdipl)2]⋅2H2O (1) and {[Cu(phen)(H2dipl)2]⋅1.25H2O}n (2) were prepared and characterized. As compared to diplacone, the complexes enhanced in vitro cytotoxicity against A2780 and A2780R human ovarian cancer cells (IC50 ≈ 0.4–1.2 μM), human lung carcinoma (A549, with IC50 ≈ 2 μM) and osteosarcoma (HOS, with IC50 ≈ 3 μM). Cellular effects of the complexes in A2780 cells were studied using flow cytometry, covering studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production. These results uncovered a possible mechanism of action characterized by the G2/M cell cycle arrest. The studies on human endothelial cells revealed that complexes 1 and 2, as well as their parental compound diplacone, do possess anti-inflammatory activity in terms of NF-κB inhibition. As for the effects on PPARα and/or PPARγ, complex 2 reduced the expression of leukocyte adhesion molecules VCAM-1 and E-selectin suggesting its dual anti-inflammatory capacity. A wide variety of Cu-containing coordination species and free diplacone ligand were proved by mass spectrometry studies in water-containing media, which might be responsible for multimodal effect of the complexes.

Co-treatment of silymarin and cisplatin inhibited cell proliferation, induced apoptosis in ovarian cancer.

Ovarian cancer is one of the most lethal gynecological cancers among women worldwide. Cisplatin (Cis) is an effective chemotherapeutic agent used to treat several types of cancer. Silymarin (SLM) is an extract of medicinal plant Silybum marianum (milk thistle) with anti-inflammatory, anti-angiogenesis, antioxidant, and anticancer properties used alone or in combination with other drugs. This study aimed to explore the effects of co-treatment with SLM and Cis on A2780 human ovarian cancer cell lines. In this study, A2780 cells were treated with various concentrations of SLM and Cis, separately and in combination. Cell cytotoxicity, scratch, clonogenic, and flow-cytometry assays were accomplished to estimate cell viability, migration, colony formation, and apoptosis, respectively. Real-time PCR was utilized to determine the expression levels of miR-155 and miR-27a. SLM significantly reduced the proliferation of A2780 cells in a concentration- and time-dependent manner. Combination treatment with SLM and Cis was more potent than either single treatment in reducing viability, suppressing migration, inhibiting colony formation, and promoting the induction of apoptosis. Additionally, gene expression analysis revealed a significant decline in the expression levels of miR-155 and miR-27a in response to all separate and combined treatments, and co-treatment was more effective than individual treatments in altering miRNAs expression. Based on our findings, SLM boosts the anticancer activity of Cis and mitigates its side effects. Thus, the co-treatment of SLM and Cis can be proposed as a promising therapeutic strategy for further investigation.

Mechanism of Hirudin-Mediated Inhibition of Proliferation in Ovarian Cancer Cells.

To investigate the inhibitory effect of hirudin on the cell proliferation of human ovarian cancer A2780 cells by preventing thrombin and its underlying molecular mechanism. Cell Counting Kit-8 (CCK-8) method was used to detect the effect of different concentrations of hirudin and thrombin on the cell proliferation of A2780 cells. PAR-1 wild-type overexpression plasmid was constructed utilizing enzyme digestion identification, and it was transferred to A2780 cells. Sequencing and Western blot were used to detect the changes in PAR-1 protein expression. Western blot detection of PKCα protein phosphorylation in A2780 cells was performed. We also implemented quantitative PCR to detect the mRNA expression levels of epithelial-mesenchymal transition (EMT)-related genes, CDH2, Snail, and Vimentin, in A2780 cells. 1μg/ml hirudin treatment maximally inhibited the promotion of A2780 cell proliferation by thrombin. Hirudin inhibited the binding of thrombin to the N-terminus of PAR-1, hindered PKCα protein phosphorylation in A2780 cells, and downregulated the mRNA expression levels of CDH2, Snail, and Vimentin. In conclusion, hirudin inhibits the cell proliferation of ovarian cancer A2780 cells, and the underlying mechanism may be through downregulating the transcription level of EMT genes, CDH2, Snail, and Vimentin. This study indicates that hirudin may have a therapeutic potential as an anti-cancer agent for ovarian cancer.

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance.

Ovarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models. A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed. The nature of TTFields-drug interaction was dependent on the drug's underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control. By inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.

Tubuloside A Induces DNA Damage and Apoptosis in Human Ovarian Cancer A2780 Cells

Objective: Ovarian carcinoma is one of the most lethal gynecological cancers, as it responds later to diagnostic methods and therapeutic responses in advanced stages. Many phytochemical compounds have been shown to be protective against cancer. Tubuloside A (TbA) is the main compound extracted from the plant Cistanche tubulosa, and its pharmacological effects have been studied broadly. Until now, the role of TbA in human ovarian carcinoma is unknown. The goal of this study was to evaluate the effects of TbA on DNA damage and apoptosis in A2780 cell lines. Methods: Different concentrations of TbA (1, 5, 25, 50, and 100 µM) and 5- Fluorouracil (1, 5, 25, 50, and 100 µM) treated to the human ovarian cancer cell (A2780) line for 24 h. After incubation, cell viability (MTT), genotoxicity (Comet analyses), and mRNA expression analyses of apoptotic markers (Caspase-3, Bax, Bcl-2, and p53) were determined. Results: Applied doses of 50 and 100 µM of TbA and 5- Fluorouracil significantly reduced cell viability. Also, TbA increased DNA damage in A2780 cells. Additionally, TbA up-regulated the mRNA expressions of caspase-3, Bax, and p53, which are apoptosis-inducing factors, and down-regulated the expression of Bcl-2. Conclusion: These results show that the p53 and caspase-3 signaling pathways may exhibit a key role in TbA-associated effects on A2780 cells and TbA may be a potential drug aspirant for ovarian cancer therapy.

Triggering RNA Interference by Photoreduction under Red Light Irradiation.

RNA interference (RNAi) using small interfering RNAs (siRNAs) is a powerful tool to target any protein of interest and is becoming more suitable for in vivo applications due to recent developments in RNA delivery systems. To exploit RNAi for cancer treatment, it is desirable to increase its selectivity, e.g., by a prodrug approach to activate the siRNAs upon external triggering, e.g., by using light. Red light is especially well suited for in vivo applications due to its low toxicity and higher tissue penetration. Known molecular (not nanoparticle-based) red-light-activatable siRNA prodrugs rely on singlet oxygen (1O2)-mediated chemistry. 1O2 is highly cytotoxic. Additionally, one of the side products in the activation of the known siRNA prodrugs is anthraquinone, which is also toxic. We herein report on an improved redlight-activatable siRNA prodrug, which does not require 1O2 for its activation. In fact, the 5' terminus of the antisense strand is protected with an electron-rich azobenzene promoiety. It is reduced and cleaved upon red light exposure in the presence of Sn(IV)(pyropheophorbide a)dichloride acting as a catalyst and ascorbate as a bulk reducing agent. We confirmed the prodrug activation upon red light irradiation both in cell-free settings and in human ovarian cancer A2780 cells.

Astragalus Polysaccharide Mediates Immunomodulatory Effects on Crosstalk between Human Peripheral Blood Mononuclear Cells and Ovarian Cancer Cell Line.

Astragalus polysaccharide (APS) is a functional component of Astragalus membranaceus with antitumor and immunomodulatory properties. This study evaluated the effect of APS on the peripheral blood mononuclear cell (PBMC) proliferation, cytokine secretion, and regulatory T cell (Treg) induction in an in vitro coculture model of human PBMCs and A2780 human ovarian cancer cells. PBMC proliferation and Treg frequency were measured by flow cytometry. Cytokine levels were assessed by enzyme-linked immunosorbent assay. APS significantly enhanced the PBMC proliferation, reduced Treg frequency, decreased anti-inflammatory cytokines including interleukin [IL]-10, transforming growth factor beta (TGF-β), and vascular endothelial growth factor-A (VEGF-A), and increased the pro-inflammatory cytokine IL-6. These findings suggest that APS may be an effective immunomodulatory supplement for cancer therapy, particularly for ovarian cancer by enhancing antitumor immune responses.

Cytotoxicity Evaluation of Unmodified Paddlewheel Dirhodium(II,II)-Acetate/-Formamidinate Complexes and Their Axially Modified Low-Valent Metallodendrimers.

Two diphenyl formamidine ligands, four dirhodium(II,II) complexes, and three axially modified low-valent dirhodium(II,II) metallodendrimers were synthesized and evaluated as anticancer agents against the A2780, A2780cis, and OVCAR-3 human ovarian cancer cell lines. The dirhodium(II,II) complexes show moderate cytotoxic activity in the tested tumor cell lines, with acetate and methyl-substituted formamidinate compounds displaying increased cytotoxicity that is relative to cisplatin in the A2780cis cisplatin resistant cell line. Additionally, methyl- and fluoro-substituted formamidinate complexes showed comparable and increased cytotoxic activity in the OVCAR-3 cell line when compared to cisplatin. The low-valent metallodendrimers show some activity, but a general decrease in cytotoxicity was observed when compared to the precursor complexes in all but one case, which is where the more active acetate-derived metallodendrimer showed a lower IC50 value in the OVCAR-3 cell line in comparison with the dirhodium(II,II) tetraacetate.

Comparison of Ophiopogon japonicus and Liriope spicata var. prolifera from Different Origins Based on Multi-Component Quantification and Anticancer Activity.

The tuberous root of Ophiopogon japonicus (Thunb.) Ker-Gawl. is a well-known Chinese medicine also called Maidong (MD) in Chinese. It could be divided into "Chuanmaidong" (CMD) and "Zhemaidong" (ZMD), according to the geographic origins. Meanwhile, the root of Liriope spicata (Thunb.) Lour. var. prolifera Y. T. Ma (SMD) is occasionally used as a substitute for MD in the market. In this study, a reliable pressurized liquid extraction and HPLC-DAD-ELSD method was developed for the simultaneous determination of nine chemical components, including four steroidal saponins (ophiopojaponin C, ophiopogonin D, liriopesides B and ophiopogonin D'), four homoisoflavonoids (methylophiopogonone A, methylophiopogonone B, methylophiopogonanone A and methylophiopogonanone B) and one sapogenin (ruscogenin) in CMD, ZMD and SMD. The method was validated in terms of linearity, sensitivity, precision, repeatability and accuracy, and then applied to the real samples from different origins. The results indicated that there were significant differences in the contents of the investigated compounds in CMD, ZMD and SMD. Ruscogenin was not detected in all the samples, and liriopesides B was only found in SMD samples. CMD contained higher ophiopogonin D and ophiopogonin D', while the other compounds were more abundant in ZMD. Moreover, the anticancer effects of the herbal extracts and selected components against A2780 human ovarian cancer cells were also compared. CMD and ZMD showed similar cytotoxic effects, which were stronger than those of SMD. The effects of MD may be due to the significant anticancer potential of ophiopognin D' and homoisoflavonoids. These results suggested that there were great differences in the chemical composition and pharmacological activity among CMD, ZMD and SMD; thus, their origins should be carefully considered in clinical application.

The Strange Case: The Unsymmetric Cisplatin-Based Pt(IV) Prodrug [Pt(CH3COO)Cl2(NH3)2(OH)] Exhibits Higher Cytotoxic Activity with respect to Its Symmetric Congeners due to Carrier-Mediated Cellular Uptake.

The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: the organic cation transporters (OCTs) are the likely proteins involved.

Lubeluzole Repositioning as Chemosensitizing Agent on Multidrug-Resistant Human Ovarian A2780/DX3 Cancer Cells.

In a previous paper, we demonstrated the synergistic action of the anti-ischemic lubeluzole (Lube S) on the cytotoxic activity of doxorubicin (Dox) and paclitaxel in human ovarian cancer A2780 and lung cancer A549 cells. In the present paper, we extended in vitro the study to the multi-drug-resistant A2780/DX3 cell line to verify the hypothesis that the Dox and Lube S drug association may potentiate the antitumor activity of this anticancer compound also in the context of drug resistance. We also evaluated some possible mechanisms underlying this activity. We analyzed the antiproliferative activity in different cancer cell lines. Furthermore, apoptosis, Dox accumulation, MDR1 downregulation, ROS, and NO production in A2780/DX3 cells were also evaluated. Our results confirm that Lube S improves Dox antiproliferative and apoptotic activities through different mechanisms of action, all of which may contribute to the final antitumor effect. Moderate stereoselectivity was found, with Lube S significantly more effective than its enantiomer (Lube R) and the corresponding racemate (Lube S/R). Docking simulation studies on the ABCB1 Cryo-EM structure supported the hypothesis that Lube S forms a stable MDR1-Dox-Lube S complex, which hampers the protein transmembrane domain flipping and blocks the efflux of Dox from resistant A2780/DX3 cells. In conclusion, our in vitro studies reinforce our previous hypothesis for repositioning the anti-ischemic Lube S as a potentiating agent in anticancer chemotherapy.

Anti-Proliferative Acyl Phenols and Arylnonanoids from the Fruit Rind of Myristica malabarica Lam.

Phytochemical investigation of the methanol extract of the fruit rind of Myristica malabarica led to the isolation of eight known compounds that were identified as malabaricones A-D, promalabaricones B and C, 1-(2,6-dihydroxyphenyl)tetradecan-1-one, and ericanone by comparison with literature spectroscopic data. The structures of malabaricones A-D, promalabaricone B, and 1-(2,6-dihydroxyphenyl)tetradecan-1-one were confirmed by X-ray crystallography. In vitro assay of the isolated phenols indicated that they exhibited moderate anti-proliferative activity against the A2780 human ovarian cancer cell. Compounds (1, 3, 5, 6 and 7) had the most potent activities, whereas the anti-proliferative activities of compounds 2 and 4 were less potent.

Highly Charged Ru(II) Polypyridyl Complexes as Photosensitizer Agents in Photodynamic Therapy of Epithelial Ovarian Cancer Cells.

Ovarian cancer recurrence is frequent and associated with chemoresistance, leading to extremely poor prognosis. Herein, we explored the potential anti-cancer effect of a series of highly charged Ru(II)-polypyridyl complexes as photosensitizers in photodynamic therapy (PDT), which were able to efficiently sensitize the formation of singlet oxygen upon irradiation (Ru12+ and Ru22+) and to produce reactive oxygen species (ROS) in their corresponding dinuclear metal complexes with the Fenton active Cu(II) ion/s ([CuRu1]4+ and [Cu2Ru2]6+). Their cytotoxic and anti-tumor effects were evaluated on human ovarian cancer A2780 cells both in the absence or presence of photoirradiation, respectively. All the compounds tested were well tolerated under dark conditions, whereas they switched to exert anti-tumor activity following photoirradiation. The specific effect was mediated by the onset of programed cell death, but only in the case of Ru12+ and Ru22+ was preceded by the loss of mitochondrial membrane potential soon after photoactivation and ROS production, thus supporting the occurrence of apoptosis via type II photochemical reactions. Thus, Ru(II)-polypyridyl-based photosensitizers represent challenging tools to be further investigated in the identification of new therapeutic approaches to overcome the innate chemoresistance to platinum derivatives of some ovarian epithelial cancers and to find innovative drugs for recurrent ovarian cancer.

A prodrug of 3-(ferrocenylaminocarbonyloxymethyl)phenol activated by reactive oxygen species in cancer cells

Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.

Citromycin Isolated from the Antarctic Marine-Derived Fungi, Sporothrix sp., Inhibits Ovarian Cancer Cell Invasion via Suppression of ERK Signaling.

Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial–mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.

Inhibition of MEK-ERK pathway enhances oncolytic vaccinia virus replication in doxorubicin-resistant ovarian cancer

Oncolytic vaccinia virus (OVV) has been reported to induce cell death in various types of cancer; however, the oncolytic activity of OVV in drug-resistant ovarian cancer remains limited. In the present study, we established doxorubicin-resistant ovarian cancer cells (A2780-R) from the A2780 human ovarian cancer cell line. Both A2780 and A2780-R cells were infected with OVV to explore its anticancer effects. Interestingly, OVV-infected A2780-R cells showed reduced viral replication and cell death compared with A2780 cells, suggesting their resistance against OVV-induced oncolysis; to understand the mechanism underlying this resistance, we explored the involvement of protein kinases. Among protein kinase inhibitors, PD0325901, an MEK inhibitor, significantly augmented OVV replication and cell death in A2780-R cells. PD0325901 treatment increased the phosphorylation of STAT3 in A2780-R cells. Moreover, cryptotanshinone, a STAT3 inhibitor, abrogated PD0325901-stimulated OVV replication. Furthermore, trametinib, a clinically approved MEK inhibitor, increased OVV replication in A2780-R cells. Transcriptomic analysis showed that the MEK inhibitor promoted OVV replication via increasing STAT3 activation and downregulating the cytosolic DNA-sensing pathway. Combined treatment with OVV and trametinib attenuated A2780-R xenograft tumor growth. These results suggest that pharmacological inhibition of MEK reinforces the oncolytic efficacy of OVV in drug-resistant ovarian cancer.

Effects of sodium new houttuyfonate on proliferation, apoptosis and migration of A2780 cells

Objective: To observe the effects of sodium new houttuyfonate on proliferation, apoptosis and migration of human epithelial ovarian cancer A2780 cells, and to investigate the inhibition of invasion and migration of human epithelial ovarian cancer A2780 cells by regulating the expression of apoptosis-related molecules. Methods: blank group and different dose groups (100, 200, 300,400 and 500 μg·ml-1of sodium new houttuyfonate) were treated with human ovarian cancer A2780 cells for 48 h, respectively. MTT assay was used to detect cell proliferation and activity, and flow cytometry was used to detect cell proliferation inhibition rate and apoptosis rate. The cell migration was observed and the healing rate and migration rate of scratch were calculated. The mRNA expression of apoptosis-related molecules Bcl-2, Bax, VEGF and NF-κBp65 was detected by real-time PCR. Results: MTT and flow cytometry results showed that compared with blank group, the cell inhibition rate of sodium neohouttuynium was significantly increased (P<0.01), and the total cell apoptosis rate was increased (P<0.05); The results of scratch test showed that compared with blank group, the migration ability of new houttuynia sodium group was weakened, and the number of cell migration was significantly reduced. PCR results showed that compared with the blank group, the mRNA expression of VEGF, Bcl-2 and NF-κBp65 in the group of neohouttuynia sodium decreased, and the expression of Bax increased. Conclusion: sodium new houttuyfonate can inhibit proliferation and promote apoptosis of human ovarian cancer A2780 cells, and may inhibit the migration of A2780 cells by regulating the expression of apoptosis-related molecules.

Comparative NMR metabolomics of the responses of A2780 human ovarian cancer cells to clinically established Pt-based drugs.

Pt-Based drugs play a very important role in current cancer treatments; yet, their cellular and mechanistic aspects are not fully understood. NMR metabolomics provides a powerful tool to investigate the metabolic perturbations induced by Pt drugs in cancer cells and decipher their meaning in relation to the presumed molecular mechanisms. We have carried out a systematic and comparative 1H NMR metabolomics study to analyze the responses of A2780 human ovarian cancer cells to the main clinically established Pt drugs, i.e., cisplatin, carboplatin and oxaliplatin. Notably, NMR analysis revealed some moderate and consistent changes in the metabolomic profiles of A2780 cells treated with the 3 Pt drugs with respect to controls, but only very small differences among them. Beyond alterations at the level of nucleic acid precursors, the observed changes highlight in all cases the induction of a significant endoplasmic reticulum stress. Owing to the clinical relevance of platinum resistance, the behavior of a cisplatin resistant A2780 cancer cell line upon cisplatin treatment was also evaluated.

Effect of cysteine thiols on the catalytic and anticancer activity of Ru(II) sulfonyl-ethylenediamine complexes.

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1-8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h-1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2- or [(η6-biph)2Ru2(NAC-H)3]2-, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.

Anti-inflammatory and Antioxidant Properties of PLGA Nanoparticles Produced From Kombucha Extract on A2780 Human Ovarian Cancer Cell Line

Background: Anti-cancer agents encapsulated in nanoparticles (NPs) can result in higher efficiency. Kombucha is a fermented tea beverage, and previous reports support its anti-cancer properties. Objectives: The present study aimed to evaluate the anti-cancer and anti-inflammatory properties of poly (lactic-co-glycolic acid) loaded Kombucha NPs (PLGA-K-NPs) against the A2780 human ovarian cancer cell line. Methods: The antioxidant activity was analyzed using ferric reducing ability of plasma and 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) assays, along with the measurement of catalase (CAT) gene expression. The gene expression of three interleukins (IL-1β, IL-6, and IL-10) was also determined to demonstrate the anti-inflammatory properties of NPs. Results: The results revealed the antioxidant effects of PLGA-K-NPs on the studied cell lines by increasing Fe3+ reduction, inhibiting the free radical formation (P&lt;0.001), and increasing the expression of the CAT gene (P&lt;0.001). In addition, NPs could significantly elevate the gene expression of IL-10 (P&lt;0.01) as an anti-inflammatory cytokine at a 40 µg/mL concentration, while reducing the expression of IL-1β and IL-6, and inflammatory cytokines at all tested concentrations (P&lt;0.01). Conclusion: According to the obtained results, PLGA-K-NPs have anti-inflammatory and anti-oxidant properties, therefore, they can be considered as a compound in the treatment of ovarian cancer. However, it needs to be further investigated in animal studies to clarify more details.