Papers by Cristina P R Xavier
Alternative & Integrative Medicine, Oct 7, 2016
Cytokine & Growth Factor Reviews, May 1, 2023
Trends in Molecular Medicine, Jun 1, 2023
Free Radical Biology and Medicine, 2018
period, we analysed cell viability, mRNA expression, and malondialdehyde. Incubating DPSC with MV... more period, we analysed cell viability, mRNA expression, and malondialdehyde. Incubating DPSC with MVs isolated from cultures of PBMC treated with genistein protected DPSC from lysis induced by H202. This may be explained because MVs induced the expression of MnSOD and catalase. To conclude, MVs secreted by genistein-treated mononuclear cells exert a protective effect against oxidative stress in DPSC.
Free Radical Biology and Medicine, 2018
Melissa officinalis L. is commonly known in Portugal as “cidreira” and it is often used as a medi... more Melissa officinalis L. is commonly known in Portugal as “cidreira” and it is often used as a medicinal plant. The extracts of Melissa officinalis are known to have anti-inflammatory and antibacterial activities and some studies have reported antitumoral effects. This study aimed to: i) verify if five different extracts (aqueous, ethanolic, methanolic, hydromethanolic and hydroethanolic) of this plant have cell growth inhibitory activity in three human tumor cell lines (MCF-7, AGS and NCI-H460); ii) Further study the most potent extract (ethanolic) in the most sensitive cell line regarding its effect on cell morphology, cell cycle and apoptosis; iii) characterize the ethanolic extract by LC-DAD-ESI/MS regarding its phenolic composition. Results showed that the five extracts decreased cell growth in all the studied cancer cell lines, in a concentration-dependent manner. The ethanolic extract was the most potent one, in the non-small cell lung cancer cell line (NCI-H460). In addition, ...
Cancer Letters, 2021
JVP. rales. edema. SJ. creat~nmc. cardlolhoraclc raho, and the use of drgoxm. ACE mhlbllan. dnnet... more JVP. rales. edema. SJ. creat~nmc. cardlolhoraclc raho, and the use of drgoxm. ACE mhlbllan. dnnettcs and patasslum suppfemonts. Amang tho Valtdallon Set. the prodlcled EF was wilhm 0.05 PI a patroni's measured numanc value In only 44% of cases. Howover, a prodtcled EF cut pomt was found, below whrch 97 1% of patlenls had a measured EF 0 45 (spoc~f~c~ty = 89%. sea lablo). Conc/us~onsr 1) Ctmlcal featureri dtsllnguIsh a subsat of paltanfs whose EF IS almost always. 0.45. rind. 2) the other subsat, a larger group, WIII requtra acfunf measummcnt of EF II II 1s to bF, known.
Proceedings of 6th International Electronic Conference on Medicinal Chemistry, 2020
Repurposing "old" drugs is an attractive strategy for cancer drug discovery, particularly for can... more Repurposing "old" drugs is an attractive strategy for cancer drug discovery, particularly for cancers with limited chemotherapeutic options and/or high therapy resistance, such as pancreatic ductal adenocarcinoma (PDAC). Drug resistance in PDAC is highly influenced by the tumor microenvironment, especially by macrophages. Extracellular vesicles (EVs) released by macrophages might have a role in PDAC drug resistance, by carrying cargo from their donor macrophages. Therefore, we aimed to i) identify, in the cargo of EVs shed by macrophages, proteins responsible for decreasing sensitivity to gemcitabine (standard-based chemotherapy in PDAC) and ii) study in PDAC cells the antitumor effect of drugs clinically approved for other diseases and known to inhibit those protein targets as an off-target effect. Proteomic analysis identified Fibronectin (FN1) and Chitinase 3-like 1 (CH3IL1) as abundantly present in EVs cargo released by human macrophages. Recombinant human proteins, rhCHI3L1 and rhFN, reduced PDAC cellular sensitivity to gemcitabine through the ERK pathway. Immunohistochemistry of PDAC tumor patient samples showed that expression of FN1 and CH3IL1 was associated to high presence of macrophages. The Cancer Genome Atlas confirmed an association of CHI3L1 and FN1 gene expression with PDAC patients overall survival, gemcitabine response and macrophage infiltration. Inhibition of CHI3L1 by pentoxifylline (approved drug for peripheral arterial disease) and of FN1 by pirfenidone (an antifibrotic drug for the treatment of idiopathic pulmonary fibrosis), partially reverted gemcitabine resistance induced by the respective recombinant proteins. Additional work will be performed in xenograft mice models of PDAC, to further study the possibility of repurposing pirfenidone and pentoxifylline for PDAC treatment.
Molecules
The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on h... more The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection. A library of glycan mimetics and derivatives was selected for a virtual screening performed against both ACE2 and spike proteins. Subsequently, in vitro assays were performed on eleven of the most promising in silico compounds to evaluate: (i) their efficacy in inhibiting cell infection by SARS-CoV-2 (using the Vero CCL-81 cell line as a model), (ii) their impact on ACE2 expression (in the Vero CCL-81 and MDA-MB-231 cell lines), and (iii) their cytotoxicity in a human lung cell line (A549). We i...
Drug Resistance Updates, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apopt... more Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells
Drug Resistance Updates, 2021
Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcom... more Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and long-term tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. There is thus an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal treatment outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge about metabolism-based mechanisms conferring adaptive resistance to chemoradio and immunotherapies as well as targeted therapies. More precisely, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapyresistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapsesustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.
Cells
Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies ... more Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely parta...
Drug Resistance Updates
Drug resistance remains a major hurdle to successful cancer treatment, being accountable for appr... more Drug resistance remains a major hurdle to successful cancer treatment, being accountable for approximately 90% of cancer-related deaths. In the past years, increasing attention has been given to the role of extracellular vesicles (EVs) in the horizontal transfer of drug resistance in cancer. Indeed, many studies have described the dissemination of therapy resistance traits mediated by EVs, which may be transferred from drug resistant tumor cells to their drug sensitive counterparts. Importantly, different key players of drug resistance have been identified in the cargo of those EVs, such as drug efflux pumps, oncoproteins, antiapoptotic proteins, or microRNAs, among others. Interestingly, the EVs-mediated crosstalk between cells from the tumor microenvironment (TME) and tumor cells has emerged as another important mechanism that leads to cancer cells drug resistance. Recently, the cargo of the TME-derived EVs responsible for the transfer of drug resistance traits has also become a focus of attention. In addition, the possible mechanisms involved in drug sequestration by EVs, likely to contribute to cancer drug resistance, are also described and discussed herein. Despite the latest scientific advances in the field of EVs, this is still a challenging area of research, particularly in the clinical setting. Therefore, further investigation is needed to assess the relevance of EVs to the failure of cancer patients to drug treatment, to identify biomarkers of drug resistance in the EV's cargo, and to develop effective therapeutic strategies to surmount drug resistance. This up-to-date review summarizes relevant literature on the role of EVs in the transfer of drug resistance competences to cancer cells, and the relevance of tumor cells and of TME cells in this process. Finally, this knowledge is integrated with a discussion of possible future clinical applications of EVs as biomarkers of drug resistance.
International Journal of Molecular Sciences, 2022
Pirfenidone, an antifibrotic drug, has antitumor potential against different types of cancers. Ou... more Pirfenidone, an antifibrotic drug, has antitumor potential against different types of cancers. Our work explored whether pirfenidone sensitizes non-small cell lung cancer (NSCLC) cell lines to chemotherapeutic treatments. The cytotoxic effect of paclitaxel in combination with pirfenidone against three NSCLC cell lines (A549, NCI-H322 and NCI-H460) was evaluated using the sulforhodamine B assay. The effects of this combination on cell viability (trypan blue exclusion assay), proliferation (BrdU incorporation assay), cell cycle (flow cytometry following PI staining) and cell death (Annexin V-FITC detection assay and Western blot) were analyzed on the most sensitive cell line (NCI-H460). The cytotoxic effect of this drug combination was also evaluated against two non-tumorigenic cell lines (MCF-10A and MCF-12A). Finally, the ability of pirfenidone to sensitize NCI-H460 cells to a combination of paclitaxel plus carboplatin was assessed. The results demonstrated that pirfenidone sensitiz...
Cancers
Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and bio... more Today, innovative three-dimensional (3D) cell culture models have been proposed as viable and biomimetic alternatives for initial drug screening, allowing the improvement of the efficiency of drug development. These models are gaining popularity, given their ability to reproduce key aspects of the tumor microenvironment, concerning the 3D tumor architecture as well as the interactions of tumor cells with the extracellular matrix and surrounding non-tumor cells. The development of accurate 3D models may become beneficial to decrease the use of laboratory animals in scientific research, in accordance with the European Union’s regulation on the 3R rule (Replacement, Reduction, Refinement). This review focuses on the impact of 3D cell culture models on cancer research, discussing their advantages, limitations, and compatibility with high-throughput screenings and automated systems. An insight is also given on the adequacy of the available readouts for the interpretation of the data obta...
The anticarcinogenic potential of dietary natural compounds on colorectal carcinoma: Effects on s... more The anticarcinogenic potential of dietary natural compounds on colorectal carcinoma: Effects on signaling pathways related to cell proliferation and cell death
Pharmaceuticals
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The ... more Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-effic...
Pharmaceuticals, 2021
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The ... more Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-effic...
Uploads
Papers by Cristina P R Xavier