Ovarian Carcinoma Cells Research Articles

Betulinic acid and glycyrrhetinic acid derived piperazinyl spacered rhodamine B conjugates are highly cytotoxic and necrotic

Pentacyclic triterpene-piperazine-rhodamine B conjugates with ursane or oleanane backbones have been shown in the past to be highly cytotoxic thereby acting as mitocans. Starting from betulinic acid or glycyrrhetinic acid, new analogues were now made available, and their cytotoxic activity was investigated employing several human tumor cell lines [A375 (melanoma), HT29 (colorectal carcinoma), MCF-7 (breast adenocarcinoma), A2780 (ovarian carcinoma), and for comparison NIH 3T3 (non-malignant fibroblasts)]. For these conjugates it has been established that the linking position at ring E governs the magnitude of cytotoxicity. These conjugates were still highly cytotoxic but significantly less cytotoxic than those holding a oleanane skeleton. Staining experiments showed the rhodamine B conjugates as necrotic compounds and to act as mitocans. The most active compound (8) held an EC50 = 0.04 μM for A2780 ovarian carcinoma cells.

Circ TYMP1 Inhibits Carcinogenesis and Cisplatin Resistance in Ovarian Cancer by Reducing Smad2/3 Phosphorylation via a MicroRNA-182A-3p/TGF1B Axis.

TYMP1 is a cancer driver in several human malignancies. However, its significance in ovarian cancer (ovarian carcinoma) remains uncertain. This research aims to understand the TYMP1's role in ovarian carcinoma carcinogenesis and cisplatin (DDP) resistance and its molecular ovarian marchionesses. Circ TYMP1 overexpression in ovarian carcinoma samples led to an accelerated tumor stage. Bioinformatics identified miR-182A-3p as the TYMP1's target transcript. Circ TYMP1 functioned as a sponge for miR-182A-3p, lowering its inhibitory effect on TGF1B. Downregulating circ TYMP1 decreased A2780-Res cell proliferation, invasion, and death resistance. Malignant ovarian carcinoma cells recovered following miR-182A-3p downregulation. TGF1B overexpression boosted A2780-Res cell proliferation, aggression, and cisplatin resistance while reducing Smad2/3 phosphorylation. TYMP1 sequesters miR-182A-3p and promotes TGF1B in ovarian carcinoma, boosting carcinogenesis and cisplatin resistance. This might lead to novel ovarian carcinoma treatments.

Potent and selective anticancer activity of half-sandwich ruthenium and osmium complexes with modified curcuminoid ligands.

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of a long hydrophobic chain obtained by replacing the OH-groups, present in curcumin and bisdemethoxycurcumin, with the palmitic acid ester. We report the synthesis of ruthenium(II) and osmium(II) p-cymene derivatives containing palmitic acid curcumin ester ligands ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene)dipalmitate (p-curcH) and ((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(4,1-phenylene)dipalmitate (p-bdcurcH). Complexes [M(II)(cym)(p-curc)/(p-bdcurc)(Cl)] 1-4 (M = Ru or Os) are neutral, whereas [M(II)(cym)(p-curc)/(p-bdcurc)(PTA)][SO3CF3] 5-8 are salts obtained when the chloride ligand is replaced by the PTA ligand. Stability studies performed on 1-8 in DMSO-PBS under physiological conditions (pH = 7.4) indicate that the complexes remain intact. The complexes exhibit potent and selective cytotoxic activity against an ovarian carcinoma cell line and its cisplatin-resistant form (A2780 and A2780cis), and non-cancerous human embryonic kidney (HEK293T) cells. To define the structure-activity relationships (SAR), the compounds have been compared with other Ru(II) and Os(II) complexes with curcuminoid ligands previously reported. SAR data reveal that the bisdemethoxycurcumin complexes are generally more active and selective than analogous curcumin-containing complexes.

Fine-tuning of the pharmacological potential of novel thiazolium ionic liquids by anion alteration.

A novel series of thiazolium ionic liquids (TILs) bound to chloride (2a–c), tetrafluoroborate (BF4) (3a–c), and bis-(trifluoromethanesulfonimide) (Tf2N) anions (4a–c) was synthesized and their physicochemical characteristics were investigated using various microanalytical techniques. The pharmacological potential of the new TILs was assessed as chemotherapeutic agents for bacterial infections and ovarian cancer (SKOV-3). Notably, ILs with the same cations become more bactericidal upon their binding with the strongest chaotropic anion (TN2f). The in vitro toxicity of the TILs toward ovarian carcinoma cell lines (SKOV-3) and normal human skin fibroblast cells (HSF) revealed that all tested TILs have the capacity to induce a dose- and time-dependent decline in SKOV-3 cell viability, with Tf2N-linked TILs (4a–c) having a preferable efficacy. In addition, the new compounds showed excellent selectivity for cancer cells (SKOV-3) over healthy cells (HSF). [iPBzTh][Tf2N] (4b) is the most cytotoxic and specific one and may act as a promising anti-ovarian cancer agent.

Synthesis and characterization of thiocarbonato-linked platinum(IV) complexes.

Herein we show the formation of new oxaliplatin-based platinum(IV) complexes by reaction with DSC-activated thiols via thiocarbonate linkage. Three model complexes based on aliphatic and aromatic thiols, as well as one complex with N-acetylcysteine as biologically active thiol were synthesized. This synthetic strategy affords the expansion of biologically active compounds other than those containing carboxylic, amine or hydroxy groups for coupling to the platinum(IV) center. The complexes were characterized by high-resolution mass spectrometry, NMR spectroscopy (1H, 13C, 195Pt) and elemental analysis. Their biological behavior was evaluated against two ovarian carcinoma cell lines and their cisplatin-resistant analogues. Remarkably, the platinum(IV) samples show modest in vitro cytotoxicity against A2780 cells and comparable effects against A2780cis cells. Two complexes in particular demonstrate improved activity against SKOV3cis cells. The reduction experiment of complex 8, investigated by UHPLC-HRMS, provides evidence of interesting platinum-species formed during reaction with ascorbic acid.

Pathways endometriosis associated ovarian cancer, a histological origin?

Endometrioid ovarian carcinoma (EnOC) and ovarian clear cell carcinoma (OCCC) are the most common endometriosis-associated ovarian cancer (EAOC) histologies. Literature suggests possible dichotomous pathways for cancer that arise from endometriosis verses those that do not, however it is not clearly defined and differences remain between histological subtypes. Additionally, the impact of endometriosis on prognosis in EAOC is varied. We aimed to explore the differences of patients with EnOC and OCCC with and without a concomitant diagnosis of endometriosis.

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

Nickel Nanoparticles Originated from Cressa Leaf Extract in the Preparation of a Novel Melem@Ni-HPA Photocatalyst for the Synthesis of Some Chromenes and a Preliminary MTT Assay on the Anticancer Activity of the Nanocomposite

Organic photochemical synthesis with visible-light has attracted much attention in recent years by academia and industrial societies due to green features of this strategy. The present study mainly focuses on the preparation of Melem@Ni-HPA nanocomposite and application of this magnetic material as an efficient photocatalyst in the fabrication of different chromenes under simple and practical conditions. The target cromenes are prepared via condensation of coumarin, aromatic aldehyde and dimedone in an open-air condition by the help of a commercial green laser in acetonitrile. Then, the structural and morphological characteristics of this new nanophotocatalyst was evaluated by routine techniques such as X-Ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), dynamic light scattering (DRS), scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDS) and vibrating-sample magnetometry (VSM). Notable advantages of this new methodology include short reaction time, cost-effectiveness, facile separation of the catalyst by a magnet, excellent performance, and acceptable atom economy. A number of contributing experimental variables are also fully attended to unravel the broadness and generality of this method. In addition, progression of the reaction seems to proceed through a radical mechanism and suggest that reactive species like •O2 – and OH• along with h+ are implicated in the photocatalytic mechanism. Reusability and stability experiments also confirmed acceptable reproducibility of the nanophotocatalyst in at least five runs. Finally, the in-vitro cellular cytotoxicity of melem@Ni-HPA nanocomposite was tested against SKOV3 human ovarian carcinoma cell line via a preliminary MTT assay. The reduction in cell viability confirmed cytotoxicity of this nanomaterial on the selected cancer cell line.

In vitro anticancer activity of eco-friendly synthesized ZnO/Ag nanocomposites

Ag nanoparticle-integrated ZnO nanoflakes (ZnO/Ag nanocomposite) were synthesized by a simple green method using Beta vulgaris (beetroot) extract and assessed for their potential in in vitro anticancer activity. Four Ag contents (2.5, 5, 7.5, and 10%) were used in the composite (ZnO/Ag-2.5, ZnO/Ag-5, ZnO/Ag-7.5, and ZnO/Ag-1.0, respectively) to examine the effects of Ag on the surface, structural, morphological, and bio-activities of the ZnO/Ag nanocomposite. Bandgap narrowing was observed due to the introduction of silver in the ZnO/Ag composites. These nanocomposites were examined for their cytotoxic effects in the cervical (HeLa) and ovarian (SKOV-3) carcinoma cell lines. The dose-dependent cytotoxicity was investigated by studying the cell viability assay, ROS generation, and adenosine triphosphate (ATP) contents when the cell lines were exposed to the ZnO/Ag composites for 48 h. Among the various ZnO/Ag composites produced, the ZnO/Ag 7.5 composite exhibited superior anticancer activity against HeLa and SKOV-3 cell lines. The Cell viability and ATP contents were reduced significantly in a dose-dependent manner, whereas ROS generation was increased appreciably.

Abstract P018: Integrative proteomics of PARP1 protein complexes and post-translational modifications implicates DDR and AKT-mTOR signaling in mediating response or primary resistance of ovarian carcinoma cells to PARP1 inhibitors

Abstract Background: About 40-50% of epithelial ovarian cancers (EOC) show defects in DNA repair by homologous recombination (HR), which are mostly associated with BRCA1/2 loss-of-function mutations. The PARP inhibitors (PARPis) olaparib, niraparib and rucaparib were recently approved for treatment of ovarian cancer patients with platinum sensitivity and recurrent ovarian cancer who carry inactivating BRCA1/2 mutations. These targeted drugs produce significant response rates ranging from 40-60% in patients with BRCA-linked advanced EOCs, but resistance is a continuing challenge. Whereas several studies have reported various mechanisms of acquired resistance to PARPis, the mechanisms of primary resistance are still poorly understood. Our goal is to develop predictors of PARPi response and to identify new targets for combination therapy to overcome primary resistance. We apply a novel integrated proteomics approach to develop mechanism-based biomarkers of response or primary resistance and to identify new therapeutic targets for rational combination approaches that can overcome resistance to single agent PARPi therapy. METHODS: The isogenic EOC cell line pair UWB1.289 with BRCA1 deletion (parental; UWB) and reconstituted with ectopic BRCA1 (UWB+B) was used. The effects of FDA approved PARPis on BRCA1-null and BRCA1-reconstituted UWB1.289 cells regarding short- and long-term cell viability were determined by CellTiterGlo and crystal violet assays. Chemical proteomics, global phosphoproteomics and ADP-ribosylation proteomics were used to identify the components of PARP1-based multiprotein complexes as well as protein post-translational modifications in the DNA damage signaling network in BRCA1/2-linked EOC cells. Specific PARP1-engaged protein complexes were further determined by immunoblotting. Frozen BRCA1-proficient and deficient ovarian cancer patient tumor samples collected at the time of debulking were also characterized by chemical proteomics. RESULTS: Cell viability assays confirmed the expected correlation between PARPi response and BRCA1/2 status. Chemical proteomics followed by validation with co-immunoprecipitation revealed differential composition of the PARP1/2-Ku70/Ku80 protein complexes in PARPi-sensitive UWB compared to UWB+B cells. Global phosphoproteomics and ADP-ribosylation proteomics further indicated that rucaparib induced the cell cycle and c-NHEJ pathways in UWB cells, but down-regulated the MAPK pathway in UWB+B cells. In addition, our results showed that inhibition of AKT PARylation and AKT-mTOR signaling may help to preserve cell viability in UWB+B cells after rucaparib treatment. Consistently, synergy with DNAPKi and AKTi was more pronounced in UWB+B cells. CONCLUSION: Ovarian cancers that do not respond to PARPi displayed significant changes in PARPi-engaged protein complexes as well as post-translational protein modifications. The combination of chemical, phospho- and ADP-ribosylation proteomics can generate a systems view of PARP1 complexes and diverse drug compensatory signaling in EOC. Citation Format: Ou Deng, Sweta Dash, Thales Nepomuceno, Bin Fang, Douglas Marchion, John Koomen, Alvaro N. Monteiro, Uwe Rix. Integrative proteomics of PARP1 protein complexes and post-translational modifications implicates DDR and AKT-mTOR signaling in mediating response or primary resistance of ovarian carcinoma cells to PARP1 inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P018.

Exploiting redox vulnerabilities to induce ovarian carcinoma cell death: a novel role for tocotrienols

Exploiting redox vulnerabilities to induce ovarian carcinoma cell death: a novel role for tocotrienols

Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer.

Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10–15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.

Splice-Variant Knock-Out of TGFβ Receptors Perturbates the Proteome of Ovarian Carcinoma Cells.

The aim of this study was to analyze the biological role of different transforming growth factor-β (TGFβ) receptor splice variants in ovarian carcinoma (OC). Specific receptor variant knockouts (KO) were prepared using the CRISPR/Cas9 genome editing system in two OC cell lines, TβRI variant 1 (TβRIv1) KO in ES-2 cells and TβRII variant 1 (TβRIIv1) KO in OVCAR-8 cells. Control and KO cells were compared by proteomic analysis, functional tests, analysis of epithelial–mesenchymal transition (EMT) drivers, and Western blot of signaling proteins. Proteomic analysis revealed significant changes in protein pathways in the KO cells. TβRIv1 KO resulted in a significant reduction in both cellular motility and invasion, while TβRIIv1 KO significantly reduced cellular motility and increased Reactive Oxygen Species (ROS) production. Both receptor variant KOs reduced MET protein levels. Of the EMT drivers, a significant decrease in TWIST protein expression, and increase in SNAIL protein and MALAT1 mRNA levels were observed in the TβRIIv1 KO compared to control. A significant decrease in JNK1 and JNK2 activation was found in the TβRIv1 KO compared to control cells. These findings provide new insight regarding the biological role of the TGFβ receptor variants in the biology and potentially the progression of OC.

Gold(I) Complexes with P-Donor Ligands and Their Biological Evaluation

Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis.

CXCL14 facilitates the growth and metastasis of ovarian carcinoma cells via activation of the Wnt/\u03b2-catenin signaling pathway

BackgroundThere is an urgent need to identify potential targets in anticancer therapy to improve the survival and prognosis of patients with ovarian cancer (OC). Herein, we investigated the functional significance of chemokine (C-X-C motif) ligand 14 (CXCL14) in OC cell growth and epithelial–mesenchymal transition (EMT).MethodsqRT PCR and western blotting was used to detect CXCL14 mRNA level and protein expression, respectively. The functional mechanism of CXCL14 in OC was investigated by CCK-8, colony formation and transwell assays. The migration ability of OC cell was determined using wound healing. The protein expressions of CXCL14 and β-catenin in OC tissues were determined by immumohistochemical staining.ResultsWe demonstrated that high levels of CXCL14 were associated with a worse prognosis in patients with OC. CXCL14 knockdown considerably restrained the growth, migration and invasion of OC cell in vitro. In contrast, ectopic CXCL14 overexpression yielded the opposite results. Investigations to determine the underlying molecular mechanisms revealed that the Wnt/β-catenin signaling pathway is involved in CXCL14-facilitated OC cell invasiveness.ConclusionThese data collectively demonstrate that CXCL14 contributes to OC cell growth and metastatic potential by regulating the Wnt/β-catenin signaling pathway.

Inhibition of Proliferation in Ovarian Cancer Cell Line (PA-1) by the Action of Green Compound "Betanin".

Ovarian carcinoma has a cure rate of 30% which makes it deadlier than any other disease. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Chemoprevention of cancer through application of natural compounds is the need of present generation as other methods are rigorous and have many side effects. Betanin, a compound from Beta vulgaris extract is used in present study to check its potential for inhibition of (PA-1) cancer cell proliferation. Determination of IC50 values through MTT assay was carried out, in addition measurement of mitochondrial membrane potential (MMP), effect of reactive oxygen species (ROS) generation, and induction of apoptosis in ovarian cancer cells through betanin was also observed. Results have shown betanin as a potential candidate for inhibition of ovarian cancer cell proliferation and it can be taken up as a serious compound for further studies for its application in cancer cure.

Betulinic acid and its spray dried microparticle formulation: In vitro PDT effect against ovarian carcinoma cell line and in vivo plasma and tumor disposition.

The race against ovarian cancer continue to motivate the research worldwide. It is known that many antitumor drugs have limited penetration into solid tumor tissues due to its microenvironment, thus contributing to their low efficacy. Therapeutic modalities have been exploited to elicit antitumor effects based on microenvironment of tumor, including Photodynamic therapy (PDT). Prospection of natural small molecules and nanotechnology are important tools in the development of new ways of obtaining photoactive compounds that are biocompatible. The Betulinic acid (BA) has shown potential biological effect as bioactive drug, but it has low water solubility. Thus, in the present study, owing to the poor solubility of the BA, its free form (BAF) was compared to a spray dried microparticle betulinic acid/HP-β-CD formulation (BAC) aiming to assess the BAF and BAC efficacy as a photosensitizer in PDT for application in ovarian cancer. BAF and BAC were submitted to assays in the presence of LED (λ=420nm) under different conditions (2.75J/cm2, 5.5J/cm2, and 11J/cm2) and in absence of irradiation, after 5min or 4h of contact with ovarian carcinoma cells (A2780) or fibroblast murine cells (3T3). Furthermore, HPLC-MS/MS and MALDI-MSI methods were developed and validated in plasma and tumor of mice proving suitable for in vivo studies. The results found a greater photoinduced cytotoxic effect for the BAC at low concentration for A2780 when irradiated with LED with similar results for fluorescence microscopy. The results motivate us to continue the studies with the BA as a potential antitumor bioactive compound.

Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma.

Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both invitro and invivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of invitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and invitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.

New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells.

Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.

Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity.

Methyl-substituted 8-hydroxyquinolines (Hquin) were successfully used to synthetize five-coordinated oxovanadium(IV) complexes: [VO(2,6-(Me)2-quin)2] (1), [VO(2,5-(Me)2-quin)2] (2) and [VO(2-Me-quin)2] (3). Complexes 1–3 demonstrated high catalytic activity in the oxidation of hydrocarbons with H2O2 in acetonitrile at 50 °C, in the presence of 2-pyrazinecarboxylic acid (PCA) as a cocatalyst. The maximum yield of cyclohexane oxidation products attained was 48%, which is high in the case of the oxidation of saturated hydrocarbons. The reaction leads to the formation of a mixture of cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone. When triphenylphosphine is added, cyclohexyl hydroperoxide is completely converted to cyclohexanol. Consideration of the regio- and bond-selectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicates that the oxidation proceeds with the participation of free hydroxyl radicals. The complexes show moderate activity in the oxidation of alcohols. Complexes 1 and 2 reduce the viability of colorectal (HCT116) and ovarian (A2780) carcinoma cell lines and of normal dermal fibroblasts without showing a specific selectivity for cancer cell lines. Complex 3 on the other hand, shows a higher cytotoxicity in a colorectal carcinoma cell line (HCT116), a lower cytotoxicity towards normal dermal fibroblasts and no effect in an ovarian carcinoma cell line (order of magnitude HCT116 > fibroblasts > A2780).