Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells

Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald–Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC₅₀ 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux.     

Assessment of salt tolerance of Nasturtium officinale R. Br. using physiological and biochemical parameters

Nasturtium officinale R. Br. seedlings were treated with a range of NaCl concentrations (0, 50, 100 and 150 mM) for 21 days after seedling emergence. Physiological analysis based on growth and mineral nutrition, showed a substantial decrease in leaf dry matter with 150 mM NaCl treatment. The growth decrease was correlated with nutritional imbalance and a reduction in potassium accumulation and transport to the leaves. At the same time, we noted an increase in leaf sodium and chloride accumulation and transport. Salt tolerance of N. officinale under 100 mM NaCl was associated with osmotic adjustment via Na⁺ and Cl^? and the maintenance of high K⁺/Na⁺ selectivity. Salt decreased carotenoid content more than chlorophylls and also disturbed membrane integrity by increasing malondialdehyde content and electrolyte leakage. At 150 mM NaCl, an increase in antioxidant enzyme-specific activities for superoxide dismutase, catalase and guaiacol peroxidase occurred in concert with a decrease in ascorbic acid, polyphenol, tannin and flavonoid content. These results indicate that N. officinale can maintain growth and natural antioxidant defense compounds such as, vitamin C, carotenoids, and polyphenols, when cultivated in 100 mM NaCl, but not at higher salt levels.     

Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments

Hypoxia and oncogene expression both stimulate glycolytic metabolism in tumors, thereby leading to lactate production. However, lactate is more than merely a by-product of glycolysis: it can be used as a metabolic fuel by oxidative cancer cells. This phenomenon resembles processes that have been described for skeletal muscle and brain that involve what are known as cell-cell and intracellular lactate shuttles. Two control points regulate lactate shuttles: the lactate dehydrogenase (LDH)-dependent conversion of lactate into pyruvate (and back), and the transport of lactate into and out of cells through specific monocarboxylate transporters (MCTs). In tumors, MCT4 is largely involved in hypoxia-driven lactate release, whereas the uptake of lactate into both tumor cells and tumor endothelial cells occurs via MCT1. Translating knowledge of lactate shuttles to the cancer field offers new perspectives to therapeutically target the hypoxic tumor microenvironment and to tackle tumor angiogenesis.     

Neural network approach to reference evapotranspiration modeling from limited climatic data in arid regions

In order to better manage the limited water resources in arid regions, accurate determination of plant water requirements is necessary. For that, the evaluation of reference evapotranspiration (ET0)--a basic component of the hydrological cycle--is essential. In this context, the Penman Monteith equation, known for its accuracy, requires a high number of climatic parameters that are not always fully available from most meteorological stations. Our study examines the effectiveness of the use of artificial neural networks (ANN) for the evaluation of ET0 using incomplete meteorological parameters. These neural networks use daily climatic data (temperature, relative humidity, wind speed and the insolation duration) as inputs, and ET0 values estimated by the Penman-Monteith formula as outputs. The results show that the proper choice of neural network architecture allows not only error minimization but also maximizes the relationship between the dependent variable and the independent variables. In fact, with a network of two hidden layers and eight neurons per layer, we obtained, during the test phase, values of 1, 1 and 0.01 for the determination coefficient, the criterion of Nash and the mean square error, respectively. Comparing results between multiple linear regression and the neural method revealed the good modeling quality and high performance of the latter, due to the possibility of improving performance criteria. In this work, we considered correlations between input variables that improve the accuracy of the model and do not pose problems of multi-collinearity. Furthermore, we succeeded in avoiding overfitting and could generalize the model for other similar areas.