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Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

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Resumen Actualmente, el cáncer pulmonar es un problema de salud importante a nivel mundial porque presenta una alta incidencia y mortalidad tanto en hombres como en mujeres. Su forma más común es el adenocarcinoma (ADC), que es una entidad patológica interesante ya que de todas las formas de cáncer pulmonar, es la que se asocia menos con el tabaquismo y un porcentaje importante de pacientes con adenocarcinoma son no fumadores. De modo que otros factores como la exposición al humo de leña, a los contaminantes del aire, la historia familiar de cáncer, entre otros, son importantes para el desarrollo del ADC pulmonar. Actualmente el ADC pulmonar es la principal forma de cáncer pulmonar en las mujeres y se ha reportado que las mujeres premenopáusicas presentan peor pronóstico y los tumores son más agresivos cuando se comparan con los hombres y las mujeres posmenopáusicas. Estos datos han sugerido el papel de los estrógenos en el cáncer pulmonar, principalmente en el ADC. Aunque existe vasta evidencia epidemiológica que demuestra esta relación, hay controversia en cuanto al papel de los estrógenos en esta patología. De igual manera no hay una opinión generalizada sobre los mecanismos por los cuales los estrógenos podrían favorecer la carcinogénesis. Sin embargo, cada vez es más clara la importancia de éstas hormonas en la carcinogénesis pulmonar. En esta revisión se muestran estos datos y se discute la relevancia de los estrógenos en el cáncer pulmonar, una patología cuya dependencia hormonal es cada vez más clara.

Abstract Lung cancer is currently a worldwide health issue because of the mortality and high incidence of this pathology in both men and women. The most common form of lung cancer is adenocarcinoma (ADC); It is an interesting disease entity because among every type of lung cancer it has the lower association with smoking and a significant percentage of patients with adenocarcinoma are not smokers. Hence other factors such as exposure to wood-smoke, air pollutants, family history of cancer, among others, are important in the development of lung ADC. Nowadays, lung ADC is the main form of lung cancer in women and reports show that premenopausal women have the worse prognosis and have more aggressive tumors compared to men and postmenopausal women. These data suggests that estrogens have a particular role in lung cancer physiopathology mainly in ADC. Although there is sufficient epidemiological evidence that indicates a relationship between sexual hormones and lung cancer, the role of estrogens in this pathology is still controversial. Furthermore there is no general consent regarding the known mechanisms by which these hormones could promote carcinogenesis and because the scarce information about the implication of these hormones in lung carcinogenesis more studies are needed. In this review we discuss the role and relevance of estrogens in lung cancer, a pathology whose hormonal dependency is becoming clearer.

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The mammary gland has long drawn the attention of the scientific community due to the limited knowledge of some fundamental aspects involved in the control of its function. Myotis velifer, a microchiropteran species, provides an interesting model to study some of the regulatory factors involved in the control of the mammary gland cycle. Having an asynchronous, monoestrous reproductive pattern, female M. velifer bats undergo drastic morphological changes of the breast during the reproductive cycle. Current research on non-chiropteran mammals indicates that serotonin (5-HT) plays a major role in the intraluminal volume homeostasis of the mammary gland during lactation; however, an analysis of both the expression and localization of the main components of the serotonergic system in the bat mammary gland is lacking. Thus, the objectives of the present study were: to describe the gross and histological anatomy of the mammary gland of M. velifer to establish the lactation period for this species; to analyze the distribution and expression of the main serotonergic components in the mammary tissues of these bats under the physiological conditions of lactation, involution and the resting phase; and to provide information on the involvement of 5-HT in the regulation of the physiological function of this organ. To assess the expression and localization of serotonergic components, multiple immunofluorescence, Western blot and HPLC methods were used. 5-HT and the enzyme that catalyzes its synthesis (TPH) were located in both myoepithelial and luminal epithelial cells, while the enzyme responsible for the catabolism of this neurohormone (MAO A) was found in luminal epithelial cells as well as in secreted products. We also found an increased expression of serotonergic components during lactation, indicating that elements of the serotonergic system may play an important role in lactation in this species of bat in a way similar to that of other mammal species.

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Preeclampsia (PE) is one of the most severe complications of pregnancy. PE is responsible for the highest rates of morbidity and mortality for both pregnant women and the neonate. In this review, we first address general aspects of PE and its diagnosis, along with some epidemiological aspects of this disease in the mexican population, in particular the experience from the Instituto Mexicano del Seguro Social. Even though over the last 20 years a great deal of evidence has accumulated regarding PE's pathophysiology, an exact mechanism to explain its etiology has not been established. This review aims to cover the status of two of the most important hypotheses in the etiology of PE: the immunological and the placental ischemia hypotheses. Recent data suggest that Natural Killer cells (NK) play a major role in the decidual spiral arteriole remodeling and in normal placental development. In genetic studies, KIR receptors present in NK cells have been involved in the susceptibility for the disease. In this review, we discuss data of our group regarding the presence of NK cells in the decidua, at the end of pregnancy and the genotypes of KIR receptors in normal and preeclamptic Mexican population. PE is characterized by abnormal placentation and hypoxia with an increase of anti-angiogenic factors; the Hypoxia-inducible factor 1-alfa (HIF1-alfa) is over expressed in PE. In this review, we also included some of our results concerning the polymorphisms and regulation of HIF in preeclamptic women.

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