scholarly journals Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis

2020 ◽  
Author(s):  
Asim Pervaiz ◽  
Michael Zepp ◽  
Rania Georges ◽  
Frank Bergmann ◽  
Saqib Mahmood ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Animal Model ◽  
Liver Metastasis ◽  
Therapeutic Target ◽  
Therapeutic Potential ◽  
Expression Profiles ◽  
Treatment Options ◽  
Disease Recurrence

Abstract Purpose Liver metastasis is observed in up to 50% of colorectal cancer (CRC) patients. Available treatment options are limited and disease recurrence is often. Chemokine receptor 5 (CCR5) has attracted attention as novel therapeutic target for treating cancers. In this study, we reinforced the importance of CCR5 as therapeutic target in CRC and its liver metastasis by applying in vitro, in vivo and clinical investigations. Methods By targeting CCR5 via siRNAs or an FDA approved antagonist (maraviroc), we investigated the ensuing antineoplastic effects in three CRC cell lines. An animal model for CRC liver metastasis was used to evaluate time-dependent expressional modulation of the CCR5 axis by cDNA microarray. The model was also used to evaluate the in vivo efficacy of targeting CCR5 by maraviroc. Circulatory and tumor associated levels of CCR5 and its cognate ligands (CCL3, CCL4, CCL5) were analyzed by ELISA, qRT-PCR and immunohistochemistry. Results Targeting the CCR5 inhibited proliferative, migratory and clonogenic properties and interfered with cell cycle-related signaling cascades. In vivo findings showed significant induction of the CCR5 axis during the early liver colonization phase. Treatment with maraviroc significantly inhibited CRC liver metastasis in the animal model. Differential expression profiles of circulatory and tumor associated CCR5/ligands were observed in CRC patients and healthy controls. Conclusion The findings indicate that targeting the CCR5 axis can be an effective strategy for treating CRC liver metastasis.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

scholarly journals LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit

Oncogene ◽  
2021 ◽  
Author(s):  
Senlin Zhao ◽  
Bingjie Guan ◽  
Yushuai Mi ◽  
Debing Shi ◽  
Ping Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Metastatic Tumor ◽  
Feedback Circuit ◽  
Colorectal Cancer Liver Metastasis ◽  
Positive Feedback Circuit

AbstractGlycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

scholarly journals Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

2020 ◽  
Vol 117 (9) ◽  
pp. 5028-5038 ◽  
Author(s):  
Evelien Houben ◽  
Kris Janssens ◽  
Doryssa Hermans ◽  
Jennifer Vandooren ◽  
Chris Van den Haute ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Treatment Options ◽  
Oncostatin M ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Human Value ◽  
Demyelinating Disorders ◽  
Downstream Mediator

The brain’s endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRβ knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRβ KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

scholarly journals Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1878 ◽  
Author(s):  
Robert H. Berndsen ◽  
Nathalie Swier ◽  
Judy R. van Beijnum ◽  
Patrycja Nowak-Sliwinska
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Chorioallantoic Membrane ◽  
Treatment Strategies ◽  
Tumor Growth Inhibition ◽  
Clinical Implementation

Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy. We have previously identified a strongly synergistic drug combination (SDC), consisting of axitinib, erlotinib, and dasatinib that is active in renal cell carcinoma cells. In this study, we investigated the activity of this SDC in different CRC cell lines (SW620, HT29, and DLD-1) in more detail. SDC treatment significantly and synergistically decreased cell metabolic activity and induced apoptosis. The translation of the in-vitro-based results to in vivo conditions revealed significant CRC tumor growth inhibition, as evaluated in the chicken chorioallantoic membrane (CAM) model. Phosphoproteomics analysis of the tested cell lines revealed expression profiles that explained the observed activity. In conclusion, we demonstrate promising activity of an optimized mixture of axitinib, erlotinib, and dasatinib in CRC cells, and suggest further translational development of this drug mixture.

scholarly journals LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yun Wang ◽  
Jia-Huan Lu ◽  
Qi-Nian Wu ◽  
Ying Jin ◽  
De-Shen Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Target ◽  
Noncoding Rna ◽  
Aerobic Glycolysis ◽  
Poor Overall Survival ◽  
Normal Tissues ◽  
In Vivo Experiments ◽  
Long Intergenic Noncoding Rna

Abstract Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

Hepatic Scaling Factors for In Vitro-In Vivo Extrapolation (IVIVE) of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis

2021 ◽  
pp. DMD-AR-2021-000359
Author(s):  
Areti-Maria Vasilogianni ◽  
Brahim Achour ◽  
Daniel Scotcher ◽  
Sheila Annie Peters ◽  
Zubida M. Al-Majdoub ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Drug Clearance ◽  
Scaling Factors ◽  
Metabolic Drug ◽  
In Vivo Extrapolation

scholarly journals ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Silvia Pietrobono ◽  
Giulia Anichini ◽  
Cesare Sala ◽  
Fabrizio Manetti ◽  
Luciana L. Almada ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Treatment Options ◽  
Blood Stream ◽  
In Vivo Studies ◽  
Melanoma Metastasis ◽  
Melanoma Invasion ◽  
Molecular Events ◽  
Transcriptional Complex

AbstractUnderstanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

scholarly journals Free Radicals Scavenging Capacity, Antidiabetic and Antihypertensive Activities of Flavonoid-Rich Fractions from Leaves ofTrichilia emeticaandOpilia amentaceain an Animal Model of Type 2 Diabetes Mellitus

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Kiessoun Konaté ◽  
Kassi Yomalan ◽  
Oksana Sytar ◽  
Patrice Zerbo ◽  
Marian Brestic ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Animal Model ◽  
Type 2 Diabetes Mellitus ◽  
Therapeutic Potential ◽  
Radical Scavenging Activity ◽  
Radical Scavenging

Trichilia emeticaandOpilia amentaceatraditional Burkinabe medicinal plants were investigated to determine their therapeutic potential to inhibit key enzymes in carbohydrate metabolism, which has relevance to the management of type 2 diabetes.In vitroandin vivoantioxidant and antihypertensive potential and antilipidemia and antihyperglycemia activities in an animal model of type 2 diabetes mellitus have been studied. The antioxidant activity of the flavonoids from leaves ofTrichilia emeticaandOpilia amentaceahas been evaluated usingβ-carotene-linoleic acid system, 1,1-diphenyl-2-picrylhydrazyl inhibitory activity, chelation of iron (II) ions, and lipid peroxidation which showed more pronounced antioxidant capacities ofTrichilia emetica. Total cholesterol concentrations decreased in an animal model of type 2 diabetes mellitus under effects of flavonoid-rich fractions from leaves ofTrichilia emeticaandOpilia amentaceahas been observed. Extract of flavonoid-rich fractions fromTrichilia emeticashown maximum radical scavenging activity and possessed marked antiamylase activity which may be due to the presence of certain secondary metabolites. Suggested better antihyperglycemia, antilipidemia, and antihypertensive properties of flavonoid-rich fractions fromTrichilia emeticacompared to the extract ofOpilia amentaceaare demonstrating antidiabetic potential ofTrichilia emeticaas therapeutic targets for the management of type 2 diabetes.

Therapeutic potential of stem cells in lung disease: progress and pitfalls

2007 ◽  
Vol 114 (2) ◽  
pp. 99-108 ◽  
Author(s):  
Michael R. Loebinger ◽  
Susana Aguilar ◽  
Sam M. Janes
Keyword(s):  
Stem Cells ◽  
Lung Disease ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Lung Parenchyma ◽  
Treatment Modalities ◽  
In Vivo Experiments ◽  
Wide Range

There has been increasing excitement over the last few years with the suggestion that exogenous stem cells may offer new treatment options for a wide range of diseases. Within respiratory medicine, these cells have been shown to have the ability to differentiate and function as both airway and lung parenchyma epithelial cells in both in vitro and increasingly in vivo experiments. The hypothesis is that these cells may actively seek out damaged tissue to assist in the local repair, and the hope is that their use will open up new cellular and genetic treatment modalities. Such is the promise of these cells that they are being rushed from the benchside to the bedside with the commencement of early clinical trials. However, important questions over their use remain and the field is presently littered with controversy and uncertainty. This review evaluates the progress made and the pitfalls encountered to date, and critically assesses the evidence for the use of stem cells in lung disease.

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