Betulinic acid suppresses NGAL-induced epithelial-to-mesenchymal transition in melanoma

Gheorgheosu, Dorina; Jung, Michaela; Ören, Bilge; Schmid, Tobias; Dehelean, Cristina; Muntean, Daniela-Lucia; Brüne, Bernhard

doi:10.1515/hsz-2013-0106

Cited by 31 publications

(26 citation statements)

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“…In contrast, the knockdown of Lcn2 in MDA-MB-231 breast cancer cells reverses EMT, associated with reduced tumour growth and metastasis [9]. In line with this, we recently described that Lcn2 conveys EMT characteristics to A375 melanoma cells, enhancing migration and invasion [15]. Moreover, the use of mouse mammary tumour Stroma-derived Lcn2 and metastasis 275 cells, whereas the possibility that Lcn2 is provided by tumour-infiltrating immune cells, such as neutrophils or macrophages, has not so far been taken into account.…”

Section: Introductionmentioning

confidence: 77%

“…In contrast, the knockdown of Lcn2 in MDA‐MB‐231 breast cancer cells reverses EMT, associated with reduced tumour growth and metastasis . In line with this, we recently described that Lcn2 conveys EMT characteristics to A375 melanoma cells, enhancing migration and invasion . Moreover, the use of mouse mammary tumour models showed that Lcn2 −/− mice developed significantly fewer tumours, but differences in metastasis are still controversially discussed .…”

Section: Introductionmentioning

confidence: 77%

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Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

et al. 2016

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Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) in the tumour microenvironment on the metastatic cascade is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-to-mesenchymal transition program in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix using a 3D-spheroid model. Moreover, a global Lcn2-deficiency attenuated breast cancer metastasis both in the MMTV-PyMT breast cancer model and in a xenograft model inoculating MCF-7 cells pre-treated with supernatants from wild type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild type PyMT tumour cells into Lcn2-lacking mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as putative therapeutic target.

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Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 77%

Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

et al. 2016

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“…On account of our group expertise in the field of skin pathologies (Dehelean et al, 2013, 2016; Gheorgheosu et al, 2013; Soica et al, 2014; Danciu et al, 2015), the present study could be seen as a first step in the synthesis and characterization of the magnetic iron nanoparticles double coated with oleic acid as future carrier platforms for transdermal drug delivery in skin malignancies (melanoma and non-melanoma skin cancers, auto-immune diseases—epidermolysis bullosa acquisita). In this regard was evaluated the toxicological profile of the colloidal suspensions on human keratinocytes cell line and by applying the dermal acute test to SKH-1 hairless mice.…”

Section: Discussionmentioning

confidence: 99%

Biocompatible Colloidal Suspensions Based on Magnetic Iron Oxide Nanoparticles: Synthesis, Characterization and Toxicological Profile

et al. 2017

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The use of magnetic iron oxide nanoparticles in biomedicine has evolved intensely in the recent years due to the multiple applications of these nanomaterials, mainly in domains like cancer. The aim of the present study was: (i) to develop biocompatible colloidal suspensions based on magnetic iron oxide nanoparticles as future theranostic tools for skin pathology and (ii) to test their effects in vitro on human keratinocytes (HaCat cells) and in vivo by employing an animal model of acute dermal toxicity. Biocompatible colloidal suspensions were obtained by coating the magnetic iron oxide nanoparticles resulted during the solution combustion synthesis with a double layer of oleic acid, as innovative procedure in increasing bioavailability. The colloidal suspensions were characterized in terms of dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro effects of these suspensions were tested by means of Alamar blue assay and the noxious effects at skin level were measured using non-invasive methods. The in vitro results indicated a lack of toxicity on normal human cells induced by the iron oxide nanoparticles colloidal suspensions after an exposure of 24 h to different concentrations (5, 10, and 25 μg·mL−1). The dermal acute toxicity test showed that the topical applications of the colloidal suspensions on female and male SKH-1 hairless mice were not associated with significant changes in the quality of barrier skin function.

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“…The antitumor effects of BA are related to the downregulation of cycli D and Bcl-xL expressions [13]. Studies have demonstrated that BA shows antimetastatic effects by inhibiting epithelial mesenchymal transition (EMT) [14]. Several studies have also suggested that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells [15].…”

Section: Introductionmentioning

confidence: 99%

Approaches to Improve the Oral Bioavailability and Effects of Novel Anticancer Drugs Berberine and Betulinic Acid

et al. 2014

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BackgroundThe poor bioavailability of Berberine (BBR) and Betulinic acid (BA) limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD) mucoadhesive microparticle formulations were prepared.MethodsA patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI) permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations.ResultsPharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma Cmax concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549) tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1α, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity.ConclusionsDue to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA.

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Betulinic acid suppresses NGAL-induced epithelial-to-mesenchymal transition in melanoma

Cited by 31 publications

References 31 publications

Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

Biocompatible Colloidal Suspensions Based on Magnetic Iron Oxide Nanoparticles: Synthesis, Characterization and Toxicological Profile

Approaches to Improve the Oral Bioavailability and Effects of Novel Anticancer Drugs Berberine and Betulinic Acid

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