1,721,095 research outputs found
The MEK1/2 inhibitor pimasertib enhances gemcitabine efficacy-letter
Full text linkNo abstract available (Letter
Homozygosis Mutation in K-ras Oncogene in Primary Cell Culture from Pancreatic Ductal Adenocarcinoma. Characteristic of the Tumor or Adaptation in Vitro?
No full textLOW-DOSE RADIOTHERAPY ENHANCES CELLULAR GROWTH IN A IN VITRO MODEL FOR PANCREATIC DUCTAL ADENOCARCINOMA
No full textTRANSFECTION OF SIRNA FOR ERK1-2 IN PRIMARY PANCREATIC CANCER CELLS CULTURES BY ELECTROPORATION REDUCE THE CELL GROWTH IN VITRO
No full textPreclinical emergence of novel lactate dehydrogenase inhibitors as potent antitumor agents in hypoxic models of pancreatic cancer: molecular mechanisms underlying their synergistic interaction with gemcitabine
No full textIntroduction: Hypoxia plays a key role in pancreatic cancer
metastasis and chemoresistance. Since LDH-A constitutes a major checkpoint to ensure sufficient energy supply in
hypoxic environments, we investigated the pharmacological activity of a series of novel LDH-A inhibitors (Granchi et al, Eur J Med Chem 2011).
Methods: In vitro studies were performed in 7 pancreatic
cancer cell lines and 7 primary cultures, characterized by differential expression of LDH-A. Cytotoxicy was evaluated with sulforhodamine-B assay, whereas LDH -A modulation was
investigated by RT-PCR, Western-blot and activity assays, using also specific siRNA. Cell cycle perturbation and apoptosis
were studied with flow-cytometry, while pharmacological interaction with gemcitabine was investigated with the combination index (CI) method. Furthermore, we examined if LDH-A inhibition modulated invasiveness, expression of cancer stem cell (CSC) markers and EMT phenotype, in adherent-cells and spheroids. All these experiments were performed in both normoxic and hypoxic conditions (1% O2).
Results: LDH-A correlated with HIF-1alpha expression
and significantly increased under hypoxic conditions. The novel LDH-A inhibitors proved to be particularly effective under hypoxic conditions, with IC50s ranging from 0.1 to 0.8 μM.
These compounds induced apoptosis, affected invasiveness and spheroid growth, reducing CSC markers and EMT. Their synergistic interaction with gemcitabine (CI values<0.8) might be attributed to modulation of gemcitabine metabolism,
with increased synthesis of phosphorylated-metabolites
as detected by LC-MS/MS.
Conclusions: These data provide evidence that LDH -A
is a viable target in pancreatic cancer cells, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool for optimizing chemotherapy in hypoxic tumors
Synergistic Interaction of Novel Lactate Dehydrogenase Inhibitors with Gemcitabine in Hypoxic Models of Pancreatic Cancer
No full textHypoxia is a driving force in pancreatic cancer growth and metastasis. Since the muscle isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch from aerobic to anaerobic glycolysis, we tested a series of novel N-hydroxy-2-carboxy-substituted indoles with Ki values for LDH-A reaching the low micromolar range. LDH-A expression was detected in all the pancreatic cancer cells, and significantly increased under hypoxic conditions. The novel LDH-A inhibitors demonstrated a good antiproliferative activity, with IC50 values ranging between 9.9 and 20.3 uM in normoxic conditions, and they proved to be particularly effective under hypoxic conditions, with 100- and 2-fold reduction of IC50s in PP78 and PANC-1 cells, respectively. Furthermore, these compounds induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine (CI values < 0.5). These data provide evidence that LDH-A is a viable target in pancreatic cancer cells, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool for optimizing chemotherapy in hypoxic pancreatic tumors
Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma
No full textBackground: Inflammatory cells contribute to the growth and spread of human malignancies by producing molecules that enhance tumour invasiveness. Aims: To characterise the inflammatory infiltrate in pancreatic ductal adenocarcinoma and to analyse its contribution to angiogenesis and its prognostic relevance. Methods: Immunohistochemistry was used to identify inflammatory cells and evaluate the expression of proangiogenic and prolymphangiogenic molecules (vascular endothelial growth factor A (VEGF-A), VEGF-C, and basic fibroblast growth factor ( bFGF)) by inflammatory and cancer cells in 137 pancreatic cancers. Intratumorous microvessel density (IMD) was assessed using CD34 as an endothelial cell marker. Results: There were significantly more mast cells and macrophages in pancreatic cancers than in normal pancreas and the number of mast cells directly correlated with the presence of lymph node metastases. However, there was no relation between numbers of infiltrating inflammatory cells and the presence of chronic pancreatitis (CP)-like changes in the parenchyma surrounding the tumour. Double immunostaining revealed that both pancreatic mast cells and macrophages express VEGF-A, VEGF-C, and bFGF. These factors were also expressed in the tumour cells in many cases. The numbers of VEGF-A expressing tumour cells and bFGF expressing tumour and inflammatory cells significantly correlated with IMD. Moreover, tumours with higher IMD had higher numbers of infiltrating mast cells and macrophages. Conclusions: Mononuclear inflammatory cells of the non-specific immune response are recruited to pancreatic cancer tissues independent of the presence of CP-like changes, may influence the metastatic capacity of the cancer cells, and may contribute to the development of tumours with high angiogenic activity
Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours
No full textPreoperative suspicion of malignancy in pancreatic neuroendocrine tumours (pNETs) is mostly based on tumour size. We retrospectively reviewed the contrast enhancement pattern (CEP) of a series of pNETs on multiphasic multidetector computed tomography (MDCT), to identify further imaging features predictive of lesion aggressiveness
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