Evaluation of doxorubicin and ß-lapachone analogs as anticancer agents, a biological and computational study.

We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and ß-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new ß-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo's DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.

In Vitro Human Endometrial Cells and In Vivo Rat Model Studies Suggest That Ulipristal Acetate Impacts Endometrial Compatibility for Embryo Implantation.

BACKGROUND: Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. AIMS: To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. METHODS: In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. RESULTS: Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. CONCLUSIONS: These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

Disruptions in reproductive health, sex hormonal profiles, and hypothalamic hormone receptors content in females of the C58/J mouse model of autism.

Autism Spectrum Disorder (ASD) is characterized by differences in social communication and interaction, as well as areas of focused interests and/or repetitive behaviors. Recent studies have highlighted a higher prevalence of endocrine and reproductive disturbances among females on the autism spectrum, hinting at potential disruptions within the hypothalamus-pituitary-ovary (HPO) axis. This research aims to explore the reproductive health disparities in ASD using an animal model of autism, the C58/J inbred mouse strain, with a focus on reproductive performance and hormonal profiles compared to the C57BL/6J control strain. Our findings revealed that the estrous cycle in C58/J females is disrupted, as evidenced by a lower frequency of complete cycles and a lack of cyclical release of estradiol and progesterone compared to control mice. C58/J females also exhibited poor performance in several reproductive parameters, including reproductive lifespan and fertility index. Furthermore, estrogen receptor alpha content showed a marked decrease in the hypothalamus of C58/J mice. These alterations in the estrous cycle, hormonal imbalances, and reduced reproductive function imply dysregulation in the HPO axis. Additionally, our in-silico study identified a group of genes involved in infertility carrying single-nucleotide polymorphisms (SNPs) in the C58/J strain, which also have human orthologs associated with autism. These findings could offer valuable insights into the molecular underpinnings of neuroendocrine axis disruption and reproductive issues observed in ASD.

EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells.

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.

Astemizole, an inhibitor of ether-à-go-go-1 potassium channel, increases the activity of the tyrosine kinase inhibitor gefitinib in breast cancer cells

Abstract Background Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. Objective We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. Materials and Methods The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cytometry. Results Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Conclusions Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.

Sitios de acción inhibitoria de la prolactina sobre la síntesis de estradiol inducida por la hormona folículo estimulante en las células de la granulosa / Sites of prolactin inhibition on gonadotropin-induced estrogen production in cultured rat granulosa cells

En este estudio se investigaron los sitios probables de la acción inhibitoria de prolactina (Prl) sobre la esteroidogénesis ovárica inducida por la hormona folículo estimulante (FSH). Para esta finalidad se estudió la capacidad de cultivos primarios de células de la granulosa de la rata de sintetizar estradiol y AMPc bajo la estimulación con FSH o de activadores de la vía dependiente de AMPc en presencia de Prl humana. La participación de otros sistemas de transducción de señal como los dependientes de PKC y proteínas Gi en los mecanismos de acción inhibitoria de la Prl fue también investigada utilizando inhibidores de estos sistemas como la calfostina C y la toxina pertusis. Los resultados demostraron la habilidad de la Prl de alterar la esteroidogénesis previa y posterior a la generación de AMPc, muy probablemente por mecanismos que involucran la activación de la subunidad catalítica de la adenilato ciclasa, así como a través de interactuar con sistemas de transducción de señal dependientes de PKC y proteínas sensibles a la toxina pertusis. Nuestros resultados sugieren un mecanismo de interacción entre receptores acoplados a proteínas G con aquéllos acoplados a cinasas de tirosinas mediado muy probablemente por vías de señalización dependientes de proteínas Gi.

We studied the sites of prolactin inhibition upon FSH induced ovarian steroidogenesis and the ability of prolactin (Prl) to inhibit the synthesis of estradiol and cAMP accumulation under the stimulation of FSH or cAMP dependent activators. The participation of other signal pathways such as PKC and Gi proteins on the inhibitory actions of Prl was also investigated using calfostine C andpertusis toxin as inhibitors. Results showed a dose dependent prolactin decrease in FSH-induced estradiol and cAMP production prior and after the generation of the cyclic nucleotide by a mechanism involving the catalytic subunit of adenyl cyclase and/or through activation of PKC or by the interaction with pertusin toxin sensitive G proteins. Our results suggest a mechanism by which G protein coupled receptors are linked with those coupled with tyrosine kinase through the involvement of a Gi protein mediated mechanism.