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Hypoxia and nutrient deprivation are responsible for inducing malignant behavior in neoplastic cells. In these conditions, metabolic stress leads the cells to enhance their autophagic flux and to activate key molecules for homeostasis maintenance. Galectin-3 (Gal-3) is upregulated in pancreatic cancer and it is activated under the hypoxic atmosphere. We aimed to analyze the most effective autophagic-inducing conditions in pancreatic ductal adenocarcinoma cells and the effect exerted under these conditions in association with hypoxia on the Gal-3 expression. Gal-3 and the microtubule-associated protein light chain 3 beta (LC3) were accessed through western blot and immunofluorescence. Degradative vacuole quantification was analyzed by transmission electronic microscopy, and inhibition of Gal-3 was performed using siRNA. According to the analyses, the most effective conditions in the inducement of autophagy for PANC-1 and MIA PaCa-2 cells were nutritional deprivation and complete amino acid/glucose deprivation, respectively. PANC-1 cells presented higher Gal-3 when they were submitted to 24 h of nutritional deprivation alone and simultaneously nutritional and oxygen deprivation. Inhibition of Gal-3 causes a decrease of LC3 levels in all experimental conditions. These results confirm that Gal-3 is modulated by microenvironment factors and the possibility of Gal-3 participating in an adaptive response from PDAC cells to extreme conditions.

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Introduction: The Vismia genus belongs to the Hypericaceae family and comprises around 57 species of which 17 have been located in Venezuela. Previous investigations have been carried out in extracts as well as pure isolated compounds, revealing antimicrobial, antioxidant and anti-HIV, among other, biological activities. Objective: This investigation aims to determine the cytotoxic activity of essential oils from leaves of Vismia baccifera Triana & Planch (VBJ and VBV) and Vismia macrophylla Kunth (VM) collected in three different locations of the Venezuelan Andean region. Methods: Essential oils obtained by hydrodistillation were analyzed using gas chromatography-mass spectrometry (GC-MS) and their cytotoxic activity was analyzed following the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Human tumor cell lines from SKBr3, MCF-7 and PANC-1, two breast carcinomas and one pancreatic adenocarcinoma of ductal type, were tested with the oil samples and human dermis fibroblasts were used as non-tumor cells. Results: β-caryophyllene and trans-caryophyllene were present as major components in VBJ and VBV, respectively, while γ-bisabolene was the main component in the VM sample. Anticancer activity was observed on V. baccifera essential oil against SKBr3, MCF-7 and PANC-1. The selectivity index showed that VBV is highly selective against the SKBr3 cell line and has no activity against non-tumor cells. Conclusions: These results are considered a contribution to natural products research and may provide supportive data for future studies on cancer.

Introducción: El género Vismia pertenece a la familia Hypericaceae y comprende alrededor de 57 especies de las cuales 17 han sido ubicadas en Venezuela. Se han realizado investigaciones previas tanto en extractos como en compuestos puros aislados revelando actividad antimicrobiana, antioxidante y anti-VIH, entre otras actividades biológicas. Objetivo: El propósito de esta investigación es determinar la actividad citotóxica de los aceites esenciales de las hojas de Vismia baccifera Triana & Planch (VBJ y VBV) y Vismia macrophylla Kunth (VM) recolectadas en tres localidades de la región andina venezolana. Métodos: Aceites esenciales obtenidos por hidrodestilación fueron analizados por cromatografía de gases-espectrometría de masas y su actividad citotóxica fue analizada siguiendo el método MTT (bromuro de 3-[4,5-dimetiltiazol-2-il]-2,5-difeniltetrazolio). Los aceites esenciales fueron ensayados frente a células tumorales humanas SKBr3, MCF-7 y PANC-1, dos carcinomas de mama y un adenocarcinoma pancreático del tipo ductal, usando cultivos primarios de fibroblastos de dermis humana como células no tumorales. Resultados: β-cariofileno y trans-cariofileno estuvieron presentes como compuestos mayoritarios en VBJ y VBV, respectivamente, mientras que γ-bisaboleno fue el componente principal en la muestra VM. El aceite esencial de V. baccifera mostró actividad anticancerígena frente a SKBr3, MCF-7 y PANC-1. El índice de selectividad reveló que VBV es altamente selectivo frente a la línea celular SKBr3 y no presenta actividad contra las células no tumorales. Conclusiones: Estos resultados se consideran una contribución a la investigación de los productos naturales y los datos pueden ser de utilidad en futuras investigaciones sobre el cáncer.

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In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 µM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 µM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.

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Integrin-linked kinase (ILK) is an ankyrin repeat-containing serine-threonine protein kinase that is involved in the regulation of integrin-mediated processes such as cancer cell proliferation, migration and invasion. In this study, we examined the effect of a lentivirus-mediated knockdown of ILK on the proliferation, migration and invasion of pancreatic cancer (Panc-1) cells. Immunohistochemical staining showed that ILK expression was enhanced in pancreatic cancer tissue. The silencing of ILK in human Panc-1 cells led to cell cycle arrest in the G0/G1 phase and delayed cell proliferation, in addition to down-regulating cell migration and invasion. The latter effects were mediated by up-regulating the expression of E-cadherin, a key protein in cell adhesion. These findings indicate that ILK may be a new diagnostic marker for pancreatic cancer and that silencing ILK could be a potentially useful therapeutic approach for treating pancreatic cancer.