Miguel Vargas

By Eduardo Gómez-Conde, Miguel Ángel Vargas Mejía, María Alicia Díaz y Orea, Luis David Gómez-Cortes and Tayde Guerrero-González

The mechanisms of mitosis in higher eukaryotic organisms are very well studied; however, regarding protozoa, there are still many questions in need of an answer. Because of the complexity with which it carries out this process, many forms of mitosis exist, such as open orthomitosis, semi-open orthomitosis, semi-open pleuromitosis, closed intranuclear pleuromitosis, closed intranuclear orthomitosis, and closed extranuclear pleuromitosis. The fascinating aspect about the mitosis of Entamoeba histolytica trophozoites is that it falls out of the context of this classification, but not entirely. The Entamoeba histolytica trophozoites first carry out karyokinesis and then cytokinesis. The mitosis of this parasite is comprised of the following phases: prophase, metaphase, early and late anaphase, early and late telophase, and karyokinesis. The difference lies in the mechanism by which it carries out the distribution of the genetic material because it forms three mitotic spindles: two radial spindles that practically surround every group of chromosomes and one that we call inter microtubule-organizing centers (IMTOCs). The latter transports each group of chromosomes at each of the nucleus poles. Based on these observations, we propose that Entamoeba histolytica trophozoites carry out a type of mitosis we have called modified intranuclear pleuromitosis open.

Part of the book: Parasitology and Microbiology Research

By Paola Briseño-Díaz, Dora Emma Velez-Uriza, Pedro Cruz-Nova, Martiniano Bello Ramirez, Jose Correa-Basurto, Rosaura Hernandez-Rivas, Ma del Rocio Thompson Bonilla and Miguel Ángel Vargas Mejía

The search for new targeted therapies to improve the quality of life of patients with pancreatic cancer has taken about 30 years. Compounds that can inhibit the K-Ras4B oncoprotein signaling pathway have been sought. Taking into account that the interaction of KRas4B with PDE6δ is essential for its transport and subsequent activation in the plasma membrane, our working group identified and evaluated in vitro and in vivo small organic molecules that could act as molecular staples to stabilize the KRas4B/PDE6δ heterodimeric complex. From this group of molecules, 38 compounds with high interaction energies on the structure of the crystallized molecular complex were selected, indicating that they efficiently stabilized the molecular complex. In vitro evaluation of compounds called D14, C22, and C19 showed significant specific effects on the cell viability of pancreatic cancer cells (and not on normal cells), thus inducing death by apoptosis and significantly inhibiting the activation of the pathways, signaling AKT and ERK. In addition to these experimental findings, we were also able to detect that compounds D14 and C22 showed significant tumor growth inhibitory activity in pancreatic cancer cell-induced subcutaneous xenograft models.

Part of the book: Challenges in Pancreatic Cancer

By Martiniano Bello and Miguel Ángel Vargas Mejía

The selective α1-adrenergic receptor antagonist doxazosin is used for the treatment of hypertension. More recently, an experimental report demonstrated that this compound exhibits antiproliferative activity in breast cancer cell lines with similar inhibitory activity to gefitinib, a selective inhibitor of EGFR in the active state (EGFRAC). This experimental study provided evidence that doxazosin can be employed as an anticancer compound, however, the structural basis for its inhibitory properties is poorly understood at the atomic level. To gain insight about this molecule, molecular dynamics (MD) simulation with the molecular mechanics generalized Born surface area (MMGBSA) approach was employed to explore the structural and energetic features that guide the inhibitory properties of doxazosin and gefitinib in overexpressing EGFR/HER2 cell lines. Our result suggest that doxazosin exerts its inhibitory properties in breast cancer cell lines by targeting EGFR/HER2 but mainly HER2 in the inactive state (HER2IN), whereas gefitinib by targeting mainly EGFRAC, in line with previous literature. Decomposition of the binding affinity into individual contributions of HER2IN-doxazosin and EGFRAC-gefitinib systems detected hot spot residues but also showed polar interactions of Met801/Met793 with the quinazoline ring of both compounds. Principal component (PC) analysis revealed that the molecular recognition of the HER2IN-doxazosin system was linked to conformational changes but EGFRAC-gefitinib was not.

Part of the book: Breast Cancer

By Dayan A. Carrion-Estrada, Paola Briseño-Diaz, Sandra Delfín-Azuara, Arturo Aguilar-Rojas and Miguel Vargas

Cancer represents the leading cause of global mortality worldwide. Recent estimates have shown that approximately 25% of all cancer types exhibiting KRAS mutations, making these mutations one of the most reported so far. Given the important role played by KRas during the progression of different tumors, the search for new therapeutic compounds that can reduce the adverse effects of this oncogene becomes evident. However, discovering effective anticancer compounds is a complex and time-consuming task. These compounds should ideally exhibit potent anticancer properties at low concentrations, with minimal impact on healthy cells. The validation of potential candidates involves several stages and methods, including in vitro techniques such as cell lines or primary cell cultures grown under 2D and 3D conditions. This chapter provides a comprehensive review of in vitro methods to support the effectiveness of two compounds, C14 and P8, specifically targeting mutant KRas as potential antitumor agents. Cytotoxicity assays were employed on breast and pancreatic cancer cell lines and primary cell cultures grown in 2D and 3D conditions to evaluate the effectiveness of these compounds. The use of multiple cell culture systems provides more pertinent data, enhancing our understanding and assessment of the potential benefits of new therapeutic molecules.

Part of the book: Technologies in Cell Culture