Papers by Meyling Gonzalez
Autophagy is one of the three main mechanisms of programmed cell death[1]. One of the basis of ca... more Autophagy is one of the three main mechanisms of programmed cell death[1]. One of the basis of cancer therapy is to induce death of tumour cells. There are several clinically approved molecules that induce cell death[2,3], but unfortunately not all tumours highly resistant to cell death respond to the existing therapies. Therefore, the search for new molecules capable of inducing tumour cell death is an area of growing interest. In this context, modulators of autophagy have become very attractive in recent years. Previous work performed by some of us has shown that methanolic extracts of the medicinal mushroom Ganoderma lucidum were modulators of cellular autophagy[4]. The aim of the present work was to further understand the cellular mechanisms involved in the autophagy modulation and to identify bioactive compounds responsible for this modulation. A methanolic extract obtained by cold extraction (-20ºC) from G. lucidum was studied with respect to its ability to induce autophagy in a gastric adenocarcinoma cell line (AGS). The presence of autophagic vacuoles was observed following transfection of cells with a mCherry-LC3 expression vector and the levels of some autophagic proteins were analysed by Western Blot. Cells were also treated with the lysossomal protease inhibitors E-64d/pepstatin together with the extract, in order to confirm if the extract induced autophagy or a decrease in the autophagic flux. The levels of the autophagic proteins after this treatment were also evaluated by Western Blot. An increase in the autophagic vacuoles was observed in cells treated with the extract (concentrations corresponding to the GI50 and 2×GI50) 24h before transfection with the mCherry-LC3 vector. In addition, treatment of cells with the same concentrations of the extract for 48h induced an increase in the expression of LC3-II together with a slight reduction in the levels of p62, particularly with the highest concentration. Additionally, cells treated with the extract together with E-64d/pepstatin expressed higher levels of LC3-II and p62, when compared with cells treated only with the extract, indicating that G. lucidum caused an induction of autophagy rather than a decrease in the autophagic flux. With these results we can conclude that the methanolic extract from the mushroom G. lucidum may be a source of compounds capable of inducing autophagy. Further studies to identify the bioactive compounds present in the tested extract and responsible for such activity are still ongoing
Cells, 2021
Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MD... more Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype. EVs’ cargo may include different players of MDR, such as microRNAS and drug-efflux pumps, which may be transferred from donor MDR cells to recipient drug-sensitive counterparts. The present work aimed to: (i) compare the ability of drug-sensitive and their MDR counterpart cells to release and capture EVs and (ii) study and relate those differences with possible distinct fate of the endocytic pathway in these counterpart cells. Our results showed that MDR cells released more EVs than their drug-sensitive counterparts and also that the drug-sensitive cells captured more EVs than their MDR counterparts. This difference in the release and capture of EVs may be associated with diff...
Blood, 2008
Defects in apoptosis have been implicated in the resistance of cancer cells to a wide variety of ... more Defects in apoptosis have been implicated in the resistance of cancer cells to a wide variety of anticancer drugs. XIAP, an inhibitor of both intrinsic and extrinsic apoptotic pathways by inhibiting caspases-3, -7 and -9, has been proposed as a good molecular target for enhancing the effects of cytotoxic drugs since: it is widely expressed in human cancer cell lines and human cancer tissues; downregulation of XIAP expression enhanced the effects of chemotherapeutic agents in various cancer cell line models; XIAP expression correlates with prognosis in some cancers, including in acute myeloid leukemia. Small molecules able to inhibit XIAP have been developed. Furthermore, antisense oligonucleotide inhibitors of XIAP (AEG35156) are already in clinical trials. However, the potential chemosensitization effect of XIAP has not been thoroughly explored, both concerning different tumor models and drugs. The purpose of the current study was to investigate if downregulation of XIAP enhances t...
Cancer chemotherapy and pharmacology, Jan 16, 2018
Liposomal therapies opened the chapter of nanomedicine, in 1995, with the approval of liposomal d... more Liposomal therapies opened the chapter of nanomedicine, in 1995, with the approval of liposomal doxorubicin (Doxil) for the treatment of numerous types of cancer. For the first time, liposomes permitted the employment of potent chemotherapeutic agents with improved pharmacokinetic and pharmacodynamic profiles, with less undesired side effects. Liposomal therapies allow the drug encapsulation and more selective delivery in the tumor bed, particularly due to the enhanced permeation and retention effect. These unique characteristics explain why liposomal therapies are being increasingly considered as alternatives in cancer therapy and represent an important research field with the recent approval for clinical use and emergent formulations in clinical trials. Even so, the response rate of liposomal therapies varies between 5 and 71%, and they are still indistinguishably given to every patient. As already well-demonstrated for conventional chemotherapies and targeted therapies, there is ...
Hematology & Medical Oncology, 2017
Autophagy is a highly regulated catabolic process through which cells recycle their own constitue... more Autophagy is a highly regulated catabolic process through which cells recycle their own constituents by delivering them into lysosomes. Several studies have demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles in cells. In cancer, autophagy has been described to have paradoxical roles, acting both as tumor suppressor and as tumor promoter. In particular, it may exert different functions in response to cancer therapy, causing cancer resistance or increasing sensitivity to chemotherapeutic drugs and radiation. Therefore, autophagy could provide new means for the enhancement of antitumor drugs and radiation effectiveness.
Medicinal Chemistry Research, 2012
Our research group has been focusing in the discovery of potential antitumor small molecules base... more Our research group has been focusing in the discovery of potential antitumor small molecules based on the xanthone scaffold. However, a serious obstacle in the field of cancer therapy is the multidrug resistance (MDR) phenotype, most often caused by the overexpression of P-glycoprotein (P-gp). Another limitation to development of such drug candidates is the reduced information available about the bioavailability of these compounds. We have previously identified four interesting compounds as inhibitors of tumor cell growth namely two dihydroxyxanthones, a xanthonolignoid and a pyranoxanthone. Based on these considerations, it was our aim to: (i) investigate their effect on the P-gp activity; and (ii) estimate their intestinal absorption using Caco-2 cell monolayers as an intestinal model. An HPLC analysis from the in vitro permeation assay with Caco-2 cells monolayer was performed to predict the intestinal permeability of xanthonic derivatives. A rhodamine (Rh123) accumulation assay using P-gp overexpressing leukemia cells, K562Dox, incubated with the four xanthonic derivatives, was performed to investigate their P-gp inhibitory activity. A luminescence-based ATPase assay was performed to differentiate between competitive and noncompetitive P-gp inhibitors. The xanthonolignoid and the pyranoxanthone were found to increase the accumulation of Rh123 in K562Dox cell line, and both were acting by a noncompetitive P-gp inhibitory mechanism. Transport of the four xanthones occurred in the absorptive direction (P app , 0.012-2.8 nm/s). The behavior of the xanthonolignoid and the pyranoxanthone as P-gp inhibitors and their high apparent permeability coefficients make them promising hit compounds to pursue with further studies.
European Journal of Medicinal Chemistry, 2013
The benzopyran and dihydrobenzopyran moieties can be considered as "privileged motifs" in drug di... more The benzopyran and dihydrobenzopyran moieties can be considered as "privileged motifs" in drug discovery being good platforms for the search of new bioactive compounds. These moieties are commonly found fused to the xanthonic scaffold belonging to the biologically important family of the generally designated prenylated xanthones. Several pyranoxanthones have shown promising antitumor activity and since most of them are from natural origin, the biosynthetic pathway only allows a particular pattern of substitution which limits their structural diversity and renders any broad structureeactivity study hard to be established. Accordingly, with the aim of rationalizing the importance of the fused ring orientation and oxygenation pattern in pyranoxanthones, this study describes the synthesis of 14 new pyranoxanthones and evaluation of their cell growth inhibitory activity in four human tumor cell lines as well as their lipophilicity in two membrane models. This systematic approach allowed establishing structureeactivity and structureelipophilicity relationships for the obtained compounds in combination with 6 previously described compounds. From this work an angular pyranoxanthone scaffold emerged as particularly promising, presenting a potent cell growth inhibitory activity and suitable drug-like lipophilicity.
European Journal of Cancer, 2012
activation. Necroptosis can be excluded as the cause of increased UV sensitivity of FADD −/− cell... more activation. Necroptosis can be excluded as the cause of increased UV sensitivity of FADD −/− cells. However, cell death of wild type fibroblasts seems to be partly due to apoptosis and partly due to necroptosis. Lack of caspase 8 activation indicates that the extrinsic pathway of apoptosis is not involved in UVB-induced apoptosis of mouse embryonic fibroblasts. 438 Function and Regulation of G-protein-coupled Receptor Kinase 2 (GRK2) in Tumor Progression of Stratified Epithelia
Chemical Biology & Drug Design, 2010
Naturally occurring xanthones have been documented as having antitumor properties, with some of t... more Naturally occurring xanthones have been documented as having antitumor properties, with some of them presently undergoing clinical trials. In an attempt to improve the biological activities of dihydroxyxanthones, prenylation and other molecular modifications were performed. All the compounds reduced viable cell number in a leukemia cell line K-562, with the fused xanthone 3, 4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3, 2-b]xanthen-6-one (5) being the most potent. The pyranoxanthone 5 was particularly effective in additional leukemia cell lines (HL-60 and BV-173). Furthermore, the pyranoxanthone 5 decreased cellular proliferation and induced an S-phase cell cycle arrest. In vitro, the pyranoxanthone 5 increased the percentage of apoptotic cells which was confirmed by an appropriate response at the protein level (e.g., PARP cleavage). Using a computer screening strategy based on the structure of several anti-and pro-apoptotic proteins, it was verified that the pyranoxanthone 5 may block the binding of anti-apoptotic Bcl-xL to pro-apoptotic Bad and Bim. The structure-based screening revealed the pyranoxanthone 5 as a new scaffold that may guide the design of small molecules with better affinity profile for Bcl-xL.
Chemical Biology & Drug Design, 2013
Epstein-Barr virus (EBV) infects more than 90% of the world population. Following primary infecti... more Epstein-Barr virus (EBV) infects more than 90% of the world population. Following primary infection, Epstein-Barr virus persists in an asymptomatic latent state. Occasionally, it may switch to lytic infection. Latent EBV infection has been associated with several diseases, such as Burkitt lymphoma (BL). To date, there are no available drugs to target latent EBV, and the existing broad-spectrum antiviral drugs are mainly active against lytic viral infection. Thus, using computational molecular docking, a virtual screen of a library of small molecules, including xanthones and flavonoids (described with potential for antiviral activity against EBV), was carried out targeting EBV proteins. The more interesting molecules were selected for further computational analysis, and subsequently, the compounds were tested in the Raji (BL) cell line, to evaluate their activity against latent EBV. This work identified three novel sulfated small molecules capable of decreasing EBV levels in a BL. Therefore, the in silico screening presents a good approach for the development of new anti-EBV agents.
Applied Physics Letters, 2010
We apply broadband measurement techniques to determine the dielectric permittivity of Bi1.5Zn1.0N... more We apply broadband measurement techniques to determine the dielectric permittivity of Bi1.5Zn1.0Nb1.5O7 (BZN) thin films over the frequency range 1 kHz to 40 GHz. At room temperature, the permittivity function shows relaxation at high frequencies (~1 GHz), and as the temperature is reduced, the onset of relaxation rapidly moves to lower frequencies, reaching ~1 kHz at 100 K. The observed
This article describes a participatory research project, which explored four case studies of chil... more This article describes a participatory research project, which explored four case studies of children and young people's successful political advocacy in Nicaragua. The analysis combined a human rights-based approach and a human development approach, and included concepts of multiple settings and levels, interrelated participation spaces, children and young people's citizenship, inclusion and exclusion, democracy, advocacy and empowerment. The main problems faced by children and young people seeking to influence policy-makers were identified as adultism, dependency and lack of accountability. The research identified preconditions , participation spaces and ways of organising for effective advocacy, and facilitation methods that had proved effective. It concludes that children and young people who achieve effective advocacy are generally self-empowered, but can count on effective adult support and facilitation. They work through coordination with the authorities and not by clashing with them, but need to ensure effective follow up if they want politicians to keep their promises.
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Papers by Meyling Gonzalez