Cancer metabolism
Multidrug resistance phenotype
pH regulation
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Scopus Publications
Scopus Publications
The Dual Role of Metformin: Repurposing an Antidiabetic Drug for Cancer Therapy Flávia Barbosa, Andrea Cunha, Joana Barbosa, Juliana Faria, Odília Queirós Applied Sciences Switzerland, 2025 Maintaining glucose homeostasis is vital for normal physiological function, and any disturbance in this balance is associated with the development of degenerative and chronic diseases, like Type 2 Diabetes (T2D) and certain types of cancer, where altered glucose metabolism plays a central role. Epidemiological evidence indicates a positive association between diabetes and an increased risk of developing certain types of cancer. Such a correlation may be driven by shared risk factors, namely obesity, inflammation, and insulin resistance. The observed association between diabetes and an increased risk of certain cancers, along with the rising incidence of both diseases, has in recent years raised interest in treatments that may target both conditions. Among them, the biguanide metformin, the first-line drug prescribed for T2D, has attracted significant attention as a repurposed drug due to its potential role in cancer treatment. Metformin is a glucose-lowering drug that reduces hepatic glucose production and improves insulin sensitivity, promoting glucose uptake by the skeletal muscle, contributing to better glycemic control in individuals with T2D and prediabetic syndromes. However, beyond its metabolic effects, metformin also influences key signaling pathways involved in cell growth and survival, such as the AMP-activated protein kinase (AMPK)/mTOR axis, raising interest in its potential application as an anticancer agent. Furthermore, metformin inhibits mitochondrial complex I, disrupting cellular energy production, which is essential for cancer proliferation. This review aims to explore and clarify the multifunctional role of metformin in both T2D and cancer, focusing on the metabolic alterations observed in these diseases. It highlights how glucose metabolism dysregulation contributes to disease progression in both contexts and explores the molecular targets of metformin in each condition and its potential for dual therapeutic benefit. Finally, selected clinical trials concerning metformin use in cancer therapy, alone or in combination, will be presented, highlighting its potential to enhance treatment response, reduce resistance, and improve overall patient outcomes.
Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia Joana Pereira-Vieira, Daniela D. Weber, Sâmia Silva, Catarina Barbosa-Matos, Sara Granja, et al. Pharmaceutics, 2024 Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.
Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids Flávia Barbosa, Joana Araújo, Virgínia M. F. Gonçalves, Andreia Palmeira, Andrea Cunha, et al. International Journal of Molecular Sciences, 2024 Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs’ effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.
Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance Andrea Cunha, Patrícia M. A. Silva, Bruno Sarmento, Odília Queirós Pharmaceutics, 2023 The “Warburg effect” consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.
Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell Diana Tavares-Valente, Stefania Cannone, Maria Raffaella Greco, Tiago Miguel Amaral Carvalho, Fátima Baltazar, et al. Cancers, 2023 Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
Special Issue “Novel Developments in the Bioproduction of Biochemicals and Biomaterials” Catarina Dias de Almeida, Odília Queirós Applied Sciences Switzerland, 2022 Bioprocesses with new environmentally friendly approaches, along with new perspectives that favor a transformation from conventional production routes to sustainable alternatives, as envisioned in the UN 2030 Agenda for Sustainable Development, will play an important role in the near future [...]
Glycolytic Inhibitors Potentiated the Activity of Paclitaxel and Their Nanoencapsulation Increased Their Delivery in a Lung Cancer Model Andrea Cunha, Ana Catarina Rocha, Flávia Barbosa, Ana Baião, Patrícia Silva, et al. Pharmaceutics, 2022 Antiglycolytic agents inhibit cell metabolism and modify the tumor’s microenvironment, affecting chemotherapy resistance mechanisms. In this work, we studied the effect of the glycolytic inhibitors 3-bromopyruvate (3BP), dichloroacetate (DCA) and 2-deoxyglucose (2DG) on cancer cell properties and on the multidrug resistance phenotype, using lung cancer cells as a model. All compounds led to the loss of cell viability, with different effects on the cell metabolism, migration and proliferation, depending on the drug and cell line assayed. DCA was the most promising compound, presenting the highest inhibitory effect on cell metabolism and proliferation. DCA treatment led to decreased glucose consumption and ATP and lactate production in both A549 and NCI-H460 cell lines. Furthermore, the DCA pretreatment sensitized the cancer cells to Paclitaxel (PTX), a conventional chemotherapeutic drug, with a 2.7-fold and a 10-fold decrease in PTX IC50 values in A549 and NCI-H460 cell lines, respectively. To increase the intracellular concentration of DCA, thereby potentiating its effect, DCA-loaded poly(lactic-co-glycolic acid) nanoparticles were produced. At higher DCA concentrations, encapsulation was found to increase its toxicity. These results may help find a new treatment strategy through combined therapy, which could open doors to new treatment approaches.
