Efecto anti-tumoral de dos triterpenos aislados de una planta medicinal

Los ácidos masticadienónico (1) y 3α-OH masticadienoico (2) son los principales metabolitos secundarios aislados de la corteza de Amphipterygium adstringens. En trabajos previos se han investigado las propiedades biológicas de estos ácidos. Inicialmente, se demostró la actividad antiinflamatoria en dos modelos de inflamación aguda, carragenina y TPA (12-O-tetradecanoilphorbol-13- acetato) (Oviedo, 2004). Por otro lado, se demostró que estos compuestos inhiben la proliferación de las líneas celulares de cáncer humano (Oviedo, 2005). Respecto al mecanismo anti-tumoral recientemente se informó el efecto de 2 sobre las funciones bioenergéticas y la permeabilidad de la membrana mitocondrial (Dalla, 2012). Sin embargo, no se ha investigado su actividad anti-tumoral in vivo. En este trabajo se investigó el efecto de 1 y 2 sobre el crecimiento tumoral en un modelo murino. Los resultados de esta investigación demuestran que los ácidos 1 y 2 tienen un efecto anti-tumoral en xenotransplantes de carcinoma prostático.The masticadienonic acid (1) and 3α-OH masticadienoic acid (2) are the main secondary metabolites of the barck from Amphipterygium adstringens (Navarrete, 2006). In previous works, were investigated the biological properties of these acids. First, was demonstrated their anti-inflamatory activity by TPA (12-Otetradecanoylphorbol- 13-acetate) and carrageenan inflammatory acute models. Also, has been demonstrated that 1 and 2 compounds inhibit the proliferation of the human cancer cell lines, HCT-15 (colon), MCF-7 (breast), U-251 (CNS), PC-3 (prostate), K-562 (leukaemia), (Oviedo, 2005). Respect to the anti-tumor mechanism recently was informed the effect of 2 on bioenergetics functions and permeability of mithocondrial membrane (Dalla, 2012). However, there are no studies about anti-tumor activity of 1 and 2 in vivo. In this work we investigated the effect of 1 and 2 on growth tumor in a murine model. The results of this research showed that acids 1 and 2 have anti-tumor effect in xenografts of prostatic carcinoma

Establishment of triple-negative breast cancer cells based on BMI: A novel model in the correlation between obesity and breast cancer

IntroductionObesity has been associated with an increased risk of biologically aggressive variants in breast cancer. Women with obesity often have tumors diagnosed at later stages of the disease, associated with a poorer prognosis and a different response to treatment. Human cell lines have been derived from specific subtypes of breast cancer and have served to define the cell physiology of corresponding breast cancer subtypes. However, there are no current cell lines for breast cancer specifically derived from patients with different BMIs. The availability of those breast cancer cell lines should allow to describe and unravel functional alterations linked to these comorbidities. MethodsCell cultures were established from tumor explants. Once generated, the triple negative subtype in a patient with obesity and a patient with a normal BMI were chosen for comparison. For cellular characterization, the following assays were conducted: proliferation assays, chemo – sensitivity assays for doxorubicin and paclitaxel, wound healing motility assays, matrix invasion assays, breast cancer cell growth to estradiol by chronic exposure to leptin, induction of endothelial permeability and tumorigenic potential in athymic mice with normo - versus hypercaloric diets with an evaluation of the epithelium – mesenchymal transformation proteins.ResultsTwo different cell lines, were established from patients with breast cancer: DSG-BC1, with a BMI of 21.9 kg/m2 and DSG-BC2, with a BMI of 31.5 kg/m2. In vitro, these two cell lines show differential growth rates, motility, chemosensitivity, vascular permeability, response to leptin with an activation of the JAK2/STAT3/AKT signaling pathway. In vivo, they displayed distinct tumorigenic potential. In particular, DSG-BC2, presented higher tumorigenicity when implanted in mice fed with a hypercaloric diet.DiscussionTo our knowledge, these primary cultures are the first in vitro representation of both breast cancer and obesity. DSG – BC2 presented a more aggressive in vivo and in vitro phenotype. These results support the hypothesis that breast cancer generated in an obese metabolic state may represent a contrasting variant within the same disease. This new model will allow both further comprehension, functional studies and the analysis of altered molecular mechanisms under the comorbidity of obesity and breast cancer

Masticadienonic and 3α-OH Masticadienoic Acids Induce Apoptosis and Inhibit Cell Proliferation and Tumor Growth in Prostate Cancer Xenografts in Vivo

The triterpenes have been constituted as a group of interesting molecules as possible antitumor agents. Despite several of them not presenting a potent cytotoxic activity in vitro against cancer cells, in vivo in xenotransplant tumors studies, they show promising results. Based on the above considerations, we investigated the antitumor activity of both masticadienonic (MDA) and 3α-OH masticadienoic (3α-OH MDA) acids in a mouse prostate cancer xenograft model. Immunohistochemical assays were used to evaluate the decrease in the expression of the Proliferating Cell Nuclear Antigen (PCNA) and the Ki-67 induced by MDA and 3α-OH MDA. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to demonstrate the fragmentation of DNA. Our results showed that the two triterpenes inhibited tumor growth, had anti-proliferative effect in vivo and induced cell death by apoptosis. Collectively, our data suggested that the antitumor mechanism of MDA and 3α-OH MDA involves several molecular targets related to cell proliferation and apoptosis

Reversal of Multidrug Resistance by Morning Glory Resin Glycosides in Human Breast Cancer Cells

Reversal of multidrug resistance (MDR) by thirty resin glycosides from the morning glory family (Convolvulaceae) was evaluated in vinblastine-resistant human breast carcinoma cells (MCF-7/Vin). The effects of these amphipathic compounds on the cytotoxicity and P-glycoprotein (P-gp)-mediated MDR were estimated with the sulforhodamine B colorimetric assay. Active noncytotoxic compounds exerted a potentiation effect of vinblastine susceptibility by 1- to over 1906-fold at tested concentrations of 5 and 25 μg/mL. Murucoidin V (<b>1</b>) enhanced vinblastine activity 255-fold when incorporated at 25 μg/mL and also, based on flow cytometry, significantly increased the intracellular accumulation of rhodamine 123 with the use of reserpine as a positive control for a MDR reversal agent. Incubation of MCF-7/Vin cells with <b>1</b> caused an increase in uptake and notably lowered the efflux rate of rhodamine 123. Decreased expression of P-glycoprotein by compound <b>1</b> was detected by immunofluorescence flow cytometry after incubation with an anti-P-gp monoclonal antibody. These results suggest that resin glycosides represent potential efflux pump inhibitors for overcoming MDR in cancer therapy

Daño al ADN y niveles de radicales libres en fibroblastos de ratones jóvenes y viejos

Se evaluó el daño al ADN en cultivos primarios de fibroblastos de pulmón provenientes de ratones j��venes (2 meses) y viejos (13 meses), en presencia y ausencia de un reto por estrés oxidativo y se correlacionó este daño con los niveles de las especies reactivas del oxígeno, para contribuir a la comprensión de la relación que existe entre los niveles de especies reactivas del oxígeno y el daño al genoma con el envejecimiento celular. Este es un fenómeno complejo que se ha tratado de explicar de diversas maneras, una es la teoría del envejecimiento por radicales libres, la cual propone que este fenómeno se debe a la acumulación del daño provocado por las especies reactivas del oxígeno a lo largo de la vida del organismo. Sin embargo, existen otras teorías diferentes que obvian el estrés oxidativo y tratan de explicar el envejecimiento basándose en cambios programados de la expresión de ciertos genes.The ADN damage was evaluated in primary cultures of lung fibroblasts from young (2 months) and old (13 months) mice in the presence and absence of a challenge presented by oxidative stress. This damage was correlated with the levels of the reactive oxygen species to contribute to the understanding of the relation existing between the levels of reactive oxygen species and the damage caused by cellular aging to the genoma. This is a complex phenomenon that has been tried to explain by different ways. One of them is the theory of aging caused by free radicals, which proposes that this phenomenon results from the accumulation of the damage caused by the reactive oxygen species during the organism&#8217;s life. However, there are other theories that rule out the oxidative stress and try to explain aging on the basis of programmed changes occurring in the expression of certain genes

Effect of Sterols Isolated from Myrtillocactus geometrizans on Growth Inhibition of Colon and Breast Cancer Cells

Objective. To explore the effect of peniocerol and macdougallin on HCT-15 and MCF-7 cells proliferation, cell cycle, apoptosis, and PARP cleavage. Methods. HCT-15 and MCF-7 cells were treated with various concentrations of peniocerol and macdougallin (10–80 μM) during 24 or 48 h. Crystal Violet Assay was used to evaluate the inhibition effect. Cell cycle regulation was examined by a propidium iodide method. Cell apoptosis was detected through both Annexin–V FLUOS/PI double-labeled cytometry assays and Western blot was applied to assess PARP cleavage. Results. Peniocerol and macdougallin induced growth inhibition and apoptosis in vitro in a time- and dose-dependent manner. Moreover, peniocerol and macdougallin induced arrest of cell cycle-dependent manner and increased the proportion of cells in G0/G1 phase. PARP cleavage in HCT-15 and MCF-7 cells was induced by treatment with peniocerol and macdougallin after 36 hours. Conclusions. Our results showed that the mechanism of cytotoxicity displayed by peniocerol and macdougallin is related to cell cycle arrest and apoptosis in both cell lines. This is a significant observation because it helps to understand the way some oxysterols isolated from Myrtillocactus geometrizans develop their biological activities against cancer cells

Correction to: Long non-coding RNAs: implications in targeted diagnoses, prognosis, and improved therapeutic strategies in human non- and triple-negative breast cancer

Upon publication of the original article [1], the authors noticed that the Figs. 1, 2 and 3 were incorrectly given

Long non-coding RNAs: implications in targeted diagnoses, prognosis, and improved therapeutic strategies in human non- and triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) has been clinically difficult to manage because of tumor aggressiveness, cellular and histological heterogeneity, and molecular mechanisms’ complexity. All this in turn leads us to evaluate that tumor biological behavior is not yet fully understood. Additionally, the heterogeneity of tumor cells represents a great biomedicine challenge in terms of the complex molecular—genetical-transcriptional and epigenetical—mechanisms, which have not been fully elucidated on human solid tumors. Recently, human breast cancer, but specifically TNBC is under basic and clinical-oncology research in the discovery of new molecular biomarkers and/or therapeutic targets to improve treatment responses, as well as for seeking algorithms for patient stratification, seeking a positive impact in clinical-oncology outcomes and life quality on breast cancer patients. In this sense, important knowledge is emerging regarding several cancer molecular aberrations, including higher genetic mutational rates, LOH, CNV, chromosomal, and epigenetic alterations, as well as transcriptome aberrations in terms of the total gene-coding ribonucleic acids (RNAs), known as mRNAs, as well as non-coding RNA (ncRNA) sequences. In this regard, novel investigation fields have included microRNAs (miRNAs), as well as long ncRNAs (lncRNAs), which have been importantly related and are likely involved in the induction, promotion, progression, and/or clinical therapeutic response trackers of TNBC. Based on this, in general terms according with the five functional archetype classification, the lncRNAs may be involved in the regulation of several molecular mechanisms which include genetic expression, epigenetic, transcriptional, and/or post-transcriptional mechanisms, which are nowadays not totally understood. Here, we have reviewed the main dis-regulated and functionally non- and well-characterized lncRNAs and their likely involvement, from a molecular enrichment and mechanistic point of view, as tumor biomarkers for breast cancer and its specific histological subtype, TNBC. In reference to the abovementioned, it has been described that some lncRNA expression profiles correspond or are associated with the TNBC histological subtype, potentially granting their use for TNBC malignant progression, diagnosis, tumor clinical stage, and likely therapy. Based on this, lncRNAs have been proposed as potential biomarkers which might represent potential predictive tools in the differentiated breast carcinomas versus TNBC malignant disease. Finally, elucidation of the specific or multi-functional archetypal of lncRNAs in breast cancer and TNBC could be fundamental, as these molecular intermediary-regulator “lncRNAs” are widely involved in the genome expression, epigenome regulation, and transcriptional and post-transcriptional tumor biology, which in turn will probably represent a new prospect in clinical and/or therapeutic molecular targets for the oncological management of breast carcinomas in general and also for TNBC patients