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.

Aims: Endovascular therapy (EVT) is a highly effective stroke treatment, but it requires the administration of contrast media which puts patients at risk of acute kidney injury (AKI). AKI is associated with increased morbidity and mortality in cardiovascular patients.Methods: PubMed, Scopus, ISI and the Cochrane Library were systematically searched for observational and experimental studies assessing the occurrence of AKI in adult acute stroke patients submitted to EVT. Two independent reviewers collected study data regarding study setting, period, source of data, and AKI definition and predictors, the outcomes of interest being AKI incidence and 90-day death or dependency (modified Rankin Scale score ≥3). These outcomes were pooled using random effect models, and heterogeneity was measured using the I²statistic.Results: 22 studies were identified and included in the analysis, involving 32 034 patients. Pooled incidence of AKI was 7% (95% CI 5% to 10%), but heterogeneity was high across studies (I²=98%), and not accounted for by the definition of AKI used. The most frequently reported AKI predictors were impaired baseline renal function (5 studies) and diabetes (3 studies); 3 studies (2103 patients) reported data on death and 4 studies (2424 patients) reported data on dependency. Overall, AKI was associated with both outcomes, with ORs of 6.21 (95% CI 3.52 to 10.96) and 2.86 (95% CI 1.88 to 4.37), respectively. Heterogeneity was low for both analyses (I²=0%).Conclusions: AKI affects 7% of acute stroke patients submitted to EVT and identifies a subgroup of patients for which treatment outcomes are suboptimal, with an increased risk of death and dependency.

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.

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.

Nature represents a rich source of bioactive compounds, with flavones emerging as privileged scaffolds owing to their multiple biological activities. Their antitumor potential arises from their ability to modulate pathways implicated in cancer progression and multidrug resistance, but structural modifications are often required to improve their pharmacokinetic properties and target selectivity. Incorporating chiral moieties, such as amino acids, may improve their potency and selectivity. Herein, we report the stereoselective synthesis of 32 new chiral derivatives of flavones (CDFs) obtained by coupling four commercial flavones with the enantiomerically pure amino esters and amino acids of tryptophan and tyrosine. Overall, the amino ester derivatives showed greater antiproliferative activity than their parent flavones against four cancer cell lines. 6HF‐DTrp ( 14 ) and 7HF‐DTrp ( 18 ) demonstrated micromolar equipotent inhibition with IC50 <21 µM against all cell lines. Most CDFs preferentially affected cancer cells over nontumor HPAEpiC cells, particularly 7HF‐DTrp ( 18 ), which displayed selectivity indices above 6. Metabolic assays exposed heterogeneous effects on glucose consumption and lactate production, suggesting that CDF‐induced cytotoxicity depends on the metabolic flexibility of each tumor phenotype rather than a universal mechanism. Furthermore, in vitro and in silico studies suggest potential P‐glycoprotein (P‐gp) inhibitory activity for 6HF‐DTrp ( 14 ) and 7HF‐DTrp ( 18 ).