JQ1, a BET Inhibitor, Synergizes with Cisplatin and Induces Apoptosis in Highly Chemoresistant Malignant Pleural Mesothelioma Cells

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance-associated c-Myc and Fra-1. OBJECTIVE: We investigated if JQ1 could enhance the efficacy of cisplatin against MPM. METHODS: The antiproliferative activity of cisplatin in combination with JQ1 was assessed on MPM cell lines representative of the cellular phenotypes of this tumor (epithelioid, sarcomatoid and biphasic), and on one cisplatin resistant sub-line. The combination schedule was optimized adopting a 3Dspheroid model. Drug combination effects were correlated with cell cycle distribution and senescence- associated \u3b2-galactosidase positive cells. The expression of c-Myc and Fra-1 proteins and some apoptosis markers was assessed by immunoblotting and RT-qPCR. DNA damage and repair were evaluated by means of alkaline comet assay. RESULTS: JQ1 in combination with cisplatin elicited additive or synergistic (superadditive) antiproliferative effects on MPM cells, depending on the cell line. The combination showed tumor regression on the 3D-spheroid model. It induced increased apoptosis, along with decreased c-Myc and, sometimes, Fra-1 expression. JQ1 decreased cisplatin-induced DNA breaks in all MPM cells and increased senescence even in less proficient cells, thus enhancing the DNA Damage Response (DDR). CONCLUSION: The superadditive effect is due to c-Myc repression. The consequent DDR enhancement triggers to apoptosis induction and/or permanent growth arrest (senescence), depending on the MPM cellular context, leading to tumor regression. Thus, the pharmacological modulation of BET activity could represent a promising tool for future MPM therapy

DNA-Metallodrugs Interactions Signaled by Electrochemical Biosensors: An Overview

The interaction of drugs with DNA is an important aspect in pharmacology. In recent years, many important technological advances have been made to develop new techniques to monitor biorecognition and biointeraction on solid devices. The interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. The propensity of a given compound to interact with DNA is measured as a function of the decrease of guanine oxidation signal on a DNA electrochemical biosensor. Covalent binding at N7 of guanine, electrostatic interactions, and intercalation are the events that this kind of biosensor can detect. In this context, the interaction between a panel of antitumoral Pt-, Ru-, and Ti-based metallodrugs with DNA immobilized on screen-printed electrodes has been studied. The DNA biosensors are used for semiquantitative evaluation of the analogous interaction occurring in the biological environment

Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates

We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs

Polyanionic Biopolymers for the Delivery of Pt(II) Cationic Antiproliferative Complexes

Phenanthriplatin, that is, (SP-4-3)-diamminechlorido(phenanthridine)platinum(II) nitrate, an effective antitumor cationic Pt(II) complex, was loaded on negatively charged dextran sulfate (DS) as a model vector for drug delivery via electrostatic interactions. The free complex and the corresponding conjugate with DS were tested on two standard human tumor cell lines, namely, ovarian A2780 and colon HCT 116, and on several malignant pleural mesothelioma cell lines (namely, epithelioid BR95, mixed/biphasic MG06, sarcomatoid MM98, and sarcomatoid cisplatin-resistant MM98R). The in vitro results suggest that the conjugate releases the active metabolite phenanthriplatin with a biphasic fashion. In these experimental conditions, the conjugate is slightly less active than free phenanthriplatin; but both exhibited antiproliferative potency higher than the reference metallodrug cisplatin and were able to overcome the acquired cisplatin chemoresistance in MM98R cells

Wine Traceability with Rare Earth Elements

The traceability of foodstuffs is now a relevant aspect of the food market. Scientific research has been devoted to addressing this issue by developing analytical protocols in order to find the link between soil and food items. In this view, chemical parameters that can act as soil markers are being sought. In this work, the role of rare earth elements (REEs) as geochemical markers in the traceability of red wine is discussed. The REE distribution in samples from each step of the wine making process of Primitivo wine (produced in Southern Italy) was determined using the highly sensitive inductively coupled plasma-mass spectrometry (ICP-MS) technique. Samples analyzed include grapes, must, and wine samples after every step in the vinification process. The resulting data were compared to the REE distribution in the soil, revealing that the soil fingerprint is maintained in the intermediate products up to and including grape must. Fractionation occurs thereafter as a consequence of further external interventions, which tends to modify the REE profile

Biological activity of enantiomeric complexes [PtCl2L2](L2 is aromatic bisphosphanes and aromatic diamines)

Enantiomeric complexes of formula [PtCl(2)L(2)] [L(2) is (R)-(+)-BINAP and (S)-(-)-BINAP, where BINAP is 2,2'-bis(diphenylphosphane)-1,1'-binaphthyl, and (R)-(+)-DABN and (S)-(-)-DABN, where DABN is 1,1'-binaphthyl-2,2'-diamine], were tested for their cytotoxic activity against three cancer cell lines and for their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar experiments were carried out on prototypal complexes cisplatin and cis-[PtCl(2)(PPh(3))(2)] for comparison. Platinum complexes containing phosphanes proved less cytotoxic to cancer cell lines and less likely to interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-(-) isomer was more active than the R-(+) counterpart. More specifically, whereas all the platinum complexes were able to platinate the G-quadruplex structure from the human telomeric repeat, the extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky) phosphanes interacted only with the adenines of the loops, whereas those containing the less sterically demanding amines interacted with adenines and some guanines of the G-quartet

Antiproliferative activity of a series of cisplatin-based Pt(IV)-acetylamido/carboxylato prodrugs

We report studies of a novel series of Pt(IV) complexes exhibiting an asymmetric combination of acetylamido and carboxylato ligands in the axial positions. We demonstrate efficient synthesis of a series of analogues, differing in alkyl chain length and hence lipophilicity, from a stable acetylamido/hydroxido complex formed by reaction of cisplatin with peroxyacetimidic acid (PAIA). NMR spectroscopy and X-ray crystallography confirm the identity of the resulting complexes, and highlight subtle differences in structure and stability of acetylamido complexes compared to equivalent acetato complexes. Reduction of acetylamido complexes, whether achieved chemically or electro-chemically, is significantly more difficult than of acetate complexes, resulting in lower antiproliferative activity for shorter-chain complexes. For those with longer chains and hence greater cell uptake, this difference is negated and acetylamido complexes are as active as acetato analogues, both exhibiting antiproliferative potency (1/IC50) against A2780 ovarian cancer cells similar to that of cisplatin

Antioxidant Composition of a Selection of Italian Red Wines and Their Corresponding Free-Radical Scavenging Ability

This study correlates the antioxidant composition profiles and the overall antioxidant capacities of 36 Italian red wine samples. The samples were fully characterized by chromatographic and spectrophotometric techniques. The overall antioxidant capacity was determined by titrating a solution of the semistable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl) with each wine sample followed by Electron Paramagnetic Resonance (EPR) spectroscopy and then measuring the resulting decrease in DPPH-signal. The antioxidant activities of the samples were expressed as (+)-catechin equivalents and related to their antioxidant composition profiles. Samples with a high polyphenol content showed a high DPPH scavenging ability as well. Seven well-defined groups, mainly constituted by wines coming from the same cultivar, were evidenced by PCA analysis. Alcohol content and pH did not influence the wine DPPH scavenging ability. The most important variables contributing to the wines’ antioxidant power are total flavonoid, total phenol, and proanthocyanidin indices together with fertaric acid, trans-caftaric acid, trans-coutaric acid, and both quercetin glucoside and quercetin glucuronide. EPR is demonstrated to be faster than the other analytical methods (spectrophotometric and chromatographic analyses) to determine the wine overall antioxidant activity

Synthesis, characterization and antiproliferative activity on mesothelioma cell lines of bis(carboxylato)platinum(IV) complexes based on picoplatin

The synthesis and characterization of a series of picoplatin-based ( picoplatin = [PtCl2(mpy)(NH3)], mpy = 2-methylpyridine), Pt(IV) complexes with axial carboxylato ligands of increasing length are reported. The synthesis is based on the oxidation with hydrogen peroxide of picoplatin to give the cis,cis,trans- [PtCl2(mpy)(NH3)(OH)2] intermediate and then its transformation into the dicarboxylato complexes cis, cis,trans-[PtCl2(mpy)(NH3)(RCOO)2] (R = CH3(CH2)n, n = 0-4) with the corresponding anhydride. Pt(IV) complexes with n = 0-2 were selected to be tested on four malignant pleural mesothelioma (MPM) cell lines, on human mesothelial cells (HMC), and on the cisplatin-sensitive ovarian A2780 cell line along with cisplatin as a metallo-drug reference. In general, the longer the axial chain, the more cytotoxic and selective the Pt(IV) complex is. Pt(IV) analogs show good activity on the MPM cell lines, approaching or in some case bypassing that of cisplatin and represent quite promising drug candidates for the treatment of tumors whose chemoresistance is mainly based on glutathione overexpression, such as MPM