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Marshall J.-C.A.,Laboratory of Molecular Pharmacology | Marshall J.-C.A.,Institute for Research and Innovation | Collins J.W.,Laboratory of Molecular Pharmacology | Nakayama J.,Laboratory of Molecular Pharmacology | And 10 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated.Methods The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups. Results In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P <. 001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P <. 001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy. Conclusion The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor sites. © The Author 2012. Published by Oxford University Press. All rights reserved.


PubMed | Marche Polytechnic University, University of Naples Federico II, Humanitas Cancer Center, Thoracic Oncology Unit and 3 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem-cell factor receptor, insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin receptors, histone deacetylase, mammalian target of rapamycin, and cyclin-dependent kinases may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs.


Pokorski M.,Polish Academy of Sciences | Pokorski M.,University of Opole | Rekawek A.,Polish Academy of Sciences | Zasada I.,Polish Academy of Sciences | And 2 more authors.
Advances in Experimental Medicine and Biology | Year: 2012

Reactive oxygen species favor the reductive state of iron. Antioxidation, by depleting biologically active ferrous iron, could then have a stabilizing effect, akin to hypoxia, on HIF-1α; the process which controls the genetic responses to hypoxia. However, the influence of antioxidation on the hypoxic ventilatory responses (HVR) is unclear. In this study we set out to determine the influence of mangiferin, a natural polyphenolic compound present in mango trees, with strong antioxidant and iron chelating properties, on the HVR. The study was performed in awake Wistar rats. Acute HVR to 12% and 8% FiO 2 before and 40 min after mangiferin (300 mg/kg, i.p.) pretreatment were recorded plethysmographically. We found that mangiferin significantly dampened the HVR over its course. To distinguish between the scavenging and chelating mechanisms of mangiferin we reinvestigated its effects on the HVR in a separate group of rats after chronic antecedent iron chelation with ciclopirox olamine (20 mg/kg daily for 1 week). The dampening effect on the HVR of mangiferin was preserved in the pre-chelated rats, which points to the preponderance of the antioxidant over chelating properties of mangiferin in its ventilatory effects. Although the exact determinants of mangiferin action remain unclear, the study suggests a role for oxidative signaling in the peripheral chemosensory processing of the HVR. The study also implies the possible clinical use of the antioxidant mangiferin in the regulation of lung ventilation. © Springer Science+Business Media Dordrecht 2012.


Rudkowska I.,Laval University | Rudkowska I.,Laboratory of Molecular Pharmacology | Guenard F.,Laval University | Guenard F.,Laboratory of Molecular Pharmacology | And 11 more authors.
Journal of Lipid Research | Year: 2014

Studies have shown a large interindividual variability in plasma TG response to long-chain n-3 PUFA supplementation, which may likely be attributable to genetic variability within the populations studied. The objective is to compare the frequency of SNPs in a genome-wide association study between responders (reduction in plasma TG levels ? 0.01 mM) and nonresponders (increase in plasma TG of ? 0 mM) to supplementation. Genomic DNA from 141 subjects who completed a 2-week run-in period followed by 6-week supplementation with 5 g of fi sh oil daily (1.9-2.2 g EPA and 1.1 g DHA daily) were genotyped on Illumina HumanOmni- 5-QuadBeadChip. Thirteen loci had frequency differences between responders and nonresponders ( P > 1 × 10 = 5 ), including SNPs in or near IQCJ-SCHIP1 , MYB , NELL1 , NXPH1 , PHF17 , and SLIT2 genes. A genetic risk score (GRS) was constructed by summing the number of risk alleles. This GRS explained 21.53% of the variation in TG response to n-3 PUFA supplementation when adjusted for age, sex, and BMI ( P = 0.0002). Using Fish Oil Intervention and Genotype as a replication cohort, the GRS was able to explain 2% of variation in TG response when adjusted. In conclusion, subjects who decrease their plasma TG levels following n-3 PUFA supplementation may have a different genetic profi le than individuals who do not respond. -Rudkowska, I., F. Guénard, P. Julien, P. Couture, S. Lemieux, O. Barbier, P. C. Calder, A. M. Minihane, and M-C. Vohl. Genome-wide © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.


Serpico D.,Thoracic Oncology Unit | Trama A.,Fondazione IRCCS Instituto Nazionale dei Tumori | Haspinger E.R.,Thoracic Oncology Unit | Agustoni F.,Thoracic Oncology Unit | And 11 more authors.
Annals of Oncology | Year: 2015

Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem-cell factor receptor, insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin receptors, histone deacetylase, mammalian target of rapamycin, and cyclin-dependent kinases may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Zajac D.,Polish Academy of Sciences | Stasinska A.,Polish Academy of Sciences | Delgado R.,Laboratory of Molecular Pharmacology | Pokorski M.,Polish Academy of Sciences
Advances in Experimental Medicine and Biology | Year: 2013

Mangiferin, the main active substance of the mango tree bark (Mangifera indica L.), is known for its use in natural medicine, not only as a health enhancing panacea or adjunct therapeutic, but also for brain functions improvement. In this context, we deemed it worthwhile to establish whether mangiferin could traverse into the brain after systemic administration; an essential piece of information for the rational use of a compound as a neurotherapeutic, remaining so far inconclusive regarding mangiferin. We addressed this issue by studying recoverability of mangiferin in membrane and cytosolic fractions of rat brain homogenates after its intraperitoneal administration in a dose of 300 mg/kg. We used three preparations of mangiferin of decreasing purity to find out whether its penetration to the brain could have to do with the possible presence of contaminants. The qualitative methods of thin-layered-chromatography and UV/VIS spectrophotometry were employed in this study. The results were clearly negative, as we failed to trace mangiferin in the brain fractions with either method, which makes it unlikely that the compound traverse the blood-brain barrier after being systemically administered. We conclude that it is improbable that mangiferin could act via direct interaction with central neural components, but rather has peripheral, target specific functions which could be secondarily reflected in brain metabolism. © 2013 Springer Science+Business Media Dordrecht.


Sabatino M.A.,Laboratory of Molecular Pharmacology
Epigenetics : official journal of the DNA Methylation Society | Year: 2013

Brostallicin is a DNA minor groove binder that shows enhanced antitumor activity in cells with high glutathione S-transferase (GST)/glutathione content. Prostate cancer cells present, almost invariably, methylation of the GSTP1 gene promoter and, as a consequence, low levels of GST-pi expression and activity. In these cells, brostallicin shows very little activity. We tested whether pretreatment of heavily GST-methylated prostate cancer cells with demethylating agents could enhance the activity of brostallicin. Human prostate cancer cells LNCaP and DU145 were used for these studies both in vitro and in vivo. The demethylating agent zebularine was used in combination with brostallicin. Methylation specific PCR and pyrosequencing were used to determine the level of GST methylation. Pretreatment with demethylating agents enhanced the in vitro activity of brostallicin in LNCaP cells. Zebularine, in particular, induced an enhancement of activity in vivo comparable to that obtained by transfecting the human GSTP1 gene in LNCaP cells in vitro. Molecular analysis performed on tumor xenografts in mice pretreated with zebularine failed to detect re-expression of GST-pi and demethylation of GSTP1. However, we found demethylation in the GSTM1 gene, with consequent re-expression of GST-mu at the mRNA level. These results indicate that zebularine, both in vitro and in vivo, enhances the activity of brostallicin and that this enhancement correlates with re-expression of GST-pi and GST-mu. These findings highlight the potential therapeutic value of combining demethylating agents and brostallicin in tumors with GST methylation that poorly respond to brostallicin.

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