Lactate in the tumor microenvironment: an essential molecule in cancer progression and treatment

Cancer is a complex disease that includes the reprogramming of metabolic pathways by malignant proliferating cells, including those affecting the tumor microenvironment (TME). The 'TME concept' was introduced in recognition of the roles played by factors other than tumor cells in cancer progression. In response to the hypoxic or semi-hypoxic characteristic of the TME, cancer cells generate a large amount of lactate via the metabolism of glucose and glutamine. Export of this newly generated lactate by the tumor cells together with H+ prevents intracellular acidification but acidifies the TME. In recent years, the importance of lactate and acidosis in carcinogenesis has gained increasing attention, including the role of lactate as a tumor-promoting metabolite. Here we review the existing literature on lactate metabolism in tumor cells and the ability of extracellular lactate to direct the metabolic reprogramming of those cells. Studies demonstrating the roles of lactate in biological processes that drive or sustain carcinogenesis (tumor promotion, angiogenesis, metastasis and tumor resistance) and lactate's role as an immunosuppressor that contributes to tumor evasion are also considered. Finally, we consider recent therapeutic efforts using available drugs directed at and interfering with lactate production and transport in cancer treatment

Immunochemical study of a transforming growth factor-α-related protein in the chicken kidney

Immunochemical study of a transforming growth factor-α-related protein in the chicken kidney. A number of polypeptides are involved in renal growth and physiology. Both transforming growth factor-α (TGF-α) protein and mRNA are expressed in kidney cells during embryonic and adult stages, and exert mitogenic activity on kidney cells in culture. We studied the immunolocalization of a TGF-α-related protein at the ultrastructural level and found it in the basolateral membranes of dark cells from distal tubules of the chicken kidney. By Western blotting techniques, we identified a protein complex composed of at least two TGF-α immunoreactive subunits of 40 and 88 kDa, respectively. Both subunits were sensitive to elastase digestion, and released TGF-α immunoreactive products. In addition, TGF-α immunoreaction was found in primary culture of chicken kidney cells. These findings suggest that the TGF-α-related protein complex plays a very specific role in proliferation and/or differentiation of kidney cells

The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition

Microbial infections are a major public health concern. Antimicrobial peptides (AMPs) have been demonstrated to be a plausible alternative to the current arsenal of drugs that has become inefficient due to multidrug resistance. Herein we describe a new AMP family, namely the super-cationic peptide dendrimers (SCPDs). Although all members of the series exert some antibacterial activity, we propose that special attention should be given to (KLK)2KLLKLL-NH2 (G1KLK-L2KL2), which shows selectivity for Gram-negative bacteria and virtually no cytotoxicity in HepG2 and HEK293. These results reinforce the validity of the SCPD family as a valuable class of AMP and support G1KLK-L2KL2 as a strong lead candidate for the future development of an antibacterial agent against Gram-negative bacteria

Synthesis and G-Quadruplex-Binding Properties of Defined Acridine Oligomers

The synthesis of oligomers containing two or three acridine units linked through 2-aminoethylglycine using solid-phase methodology is described. Subsequent studies on cell viability showed that these compounds are not cytotoxic. Binding to several DNA structures was studied by competitive dialysis, which showed a clear affinity for DNA sequences that form G-quadruplexes and parallel triplexes. The fluorescence spectra of acridine oligomers were affected strongly upon binding to DNA. These spectral changes were used to calculate the binding constants (K). Log K were found to be in the order of 4–6

Tránsito histórico de la pornografía: de transformaciones hasta la era de la internet

Internet pornography is an unprecedented phenomenon in the history of mankind. The present article seeks to exhibit a theoretical-historical review that accounts for the cultural and socio-legal transformations that allowed its conformation, while highlighting the distinctive features that separate it  qualitatively from other similar forms of eroticizing material. In a dialectical movement characterized initially by sexuality and divinity’s merging, later by a dark era of censorship and oppression, and finally by a new liberation as commodity and entertainment in the information age, pornography undergoes vertiginous transformations far ahead the study of academia, particularly in the Latin American context.La pornografía en internet se presenta como un fenómeno sin precedentes en la historia de la humanidad. Este trabajo expone una revisión teórico-histórica que da cuenta de las transformaciones culturales y sociojurídicas que permitieron su conformación, y al mismo tiempo destaca los rasgos distintivos que la separan cualitativamente de formas similares de material erotizante. En un movimiento dialéctico, caracterizado inicialmente por la unión entre sexualidad y divinidad, posteriormente por una era oscura de censura y opresión y, finalmente, por una nueva liberación como mercancía y entretenimiento en la era de la información, la pornografía ha sufrido transformaciones vertiginosas que adelantan con creces el estudio de la academia, particularmente en nuestra realidad latinoamericana

Effects of the proapoptotic drug prodigiosin on cell cycle-related proteins in Jurkat T cells

Prodigiosin (PG) is a red pigment produced by Serratia marcescens with immunosuppressive and apoptotic activities. In this study, we sought to examine the effect of PG on cell cycle-related proteins. The antiproliferative activity of PG was tested using human Jurkat leukaemia T cells in culture. PG-inhibited cell proliferation was determined using thymidine incorporation assay. PG-arrested cell cycle was analysed using immunoblot analysis with specific antibodies against cell cycle-related proteins and kinase assays of cdk2. Apoptosis was determined by Hoechst staining and analysis of DNA fragmentation. PG inhibited cyclin E, cdk2, p27 and p21, the induction of the cyclin A-cdk2 and cyclin E-cdk2 kinase activity, and the phosphorylation of Rb in leukaemic Jurkat cells. We confirmed that PG induces apoptosis by the characteristic DNA laddering pattern and condensed nuclei or apoptotic bodies identified by fluorescence microscopy. These results indicate that PG and other family members form a new group of molecules with a common mechanism of action and specific molecular targets, raising the possibility of their therapeutic use as antineoplastic drugs

Osteonecrosis de maxilares asociada al uso de bifosfonatos: revisión de 491 casos

En los últimos años, el número de pacientes que presenta osteonecrosis maxilar asociada al uso de bifosfonatos (BIONJ) se ha incrementado. Esto es debido al aumento en el consumo de bifosfonatos, los cuales se asocian al tratamiento de carcinomas con metástasis óseas, mieloma múltiple, osteoporosis, osteopenia y enfermedades metabólicas como la enfermedad de Paget. Objetivo: Analizar el número de casos de pacientes que han desarrollado osteonecrosis de maxilares asociado al uso de bifosfonatos, publicados desde Junio del año 2006 hasta Abril 2010. Método: En esta revisión, se consultaron las bases de datos Pubmed-Medline, Scielo e Índice Médico Español, incluyendo límites en la búsqueda, para recopilar los casos de BIONJ que se hayan publicado desde el año 2006 hasta la actualidad. Los artículos seleccionados presentaban casos, en los cuales los pacientes que recibían bifosfonatos desarrollaban BIONJ. Resultados: Se encontraron 491 casos de BIONJ en total, de ellos 49,3% eran mujeres, 32% hombres y 18,7% no se establecía el género. La mayoría de estos casos se presentaron en la mandíbula y asociados particularment al ácido zolendrónico. Conclusiones: En los próximos años se espera que el número de pacientes que desarrollen esta complicación vaya en aumento, en particular en mujeres, a las cuales se les indica cada vez más esta medicación para el tratamiento de la osteoporosis

Transmembrane anion transport and cytotoxicity of synthetic tambjamine analogs

Ten synthetic analogs of the marine alkaloids tambjamines, bearing aromatic enamine moieties, have been synthesized. These compounds proved to be highly efficient transmembrane anion transporters in model liposomes. Changes in the electronic nature of the substituents of the aromatic enamine or the alkoxy group of the central pyrrole group did not affect this anionophore activity. The in vitro activity of these compounds has also been studied. They trigger apoptosis in several cancer cell lines with IC50 values in the low micromolar range as well as modify the intracellular pH, inducing the basification of acidic organelles.Consejería de Educación de la Junta de Castilla y León (Project BU340U13) and Fundació la Maratón de TV3

Prodigiosin induces cell death and morphological changes indicative of apoptosis in gastric cancer cell line HGT-1

Gastric cancer is one of the most frequent malignancies and its treatment is far from satisfactory. The challenge to oncologists is the characterization of novel chemical entities with greater effectiveness. Prodigiosin is a red pigment produced by various bacteria including Serratia marcescens. Here we characterize the apoptotic action of prodigiosin in human gastric carcinoma cell line (HGT-1). Cells were assayed by the MTT assay, fragmentation pattern of DNA, Hoechst 33342 staining and study of actin microfilament architecture. Treatment of these cells with prodigiosin showed a constant decrease in viability by apoptosis. Morphological analysis of prodigiosin-treated cells demonstrated that prodigiosin induces cell shrinkage, chromatin condensation, reorganization of actin microfilament architecture, and detachment of cells from the cell culture substrate. Altogether these results suggest that prodigiosin induces apoptosis in HGT-1 human gastric cancer cells and raises the possibility of its use as a new chemotherapeutic drug

The natural-based antitumor compound T21 decreases survivin levels through potent STAT3 inhibition in lung cancer models

Lung cancer is the leading cause of cancer-related deaths worldwide; hence novel treatments for this malignancy are eagerly needed. Since natural-based compounds represent a rich source of novel chemical entities in drug discovery, we have focused our attention on tambjamines, natural compounds isolated from marine invertebrates that have shown diverse pharmacological activities. Based on these structures, we have recently identified the novel indole-based tambjamine analog 21 (T21) as a promising antitumor agent, which modulates the expression of apoptotic proteins such as survivin. This antiapoptotic protein plays an important role in carcinogenesis and chemoresistance. In this work, we have elucidated the molecular mechanism by which the anticancer compound T21 exerts survivin inhibition and have validated this protein as a therapeutic target in di erent lung cancer models. T21 was able to reduce survivin protein levels in vitro by repressing its gene expression through the blockade of Janus kinase/Signal Transducer and Activator of Transcription-3 (JAK/STAT3)/survivin signaling pathway. Interestingly, this occurred even when the pathway was overstimulated with its ligand interleukin 6 (IL-6), which is frequently overexpressed in lung cancer patients who show poor clinical outcomes. Altogether, these results show T21 as a potent anticancer compound that e ectively decreases survivin levels through STAT3 inhibition in lung cancer, appearing as a promising therapeutic drug for cancer treatment