scholarly journals Mebendazole augments sensitivity to sorafenib by targeting MAPK and BCL-2 signalling in n-nitrosodiethylamine-induced murine hepatocellular carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nancy S. Younis ◽  
Amal M. H. Ghanim ◽  
Sameh Saber
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Hepatic Inflammation ◽  
Novel Approach ◽  
Tnf Α ◽  
Mapk Signalling ◽  
Cancer Types ◽  
Tgf Β1

AbstractSorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-β1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.

scholarly journals Targeting the ERK Signaling Pathway in Melanoma

2019 ◽  
Vol 20 (6) ◽  
pp. 1483 ◽  
Author(s):  
Paola Savoia ◽  
Paolo Fava ◽  
Filippo Casoni ◽  
Ottavio Cremona
Keyword(s):  
Drug Resistance ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Clinical Trial Data ◽  
Resistance Mechanisms ◽  
Additional Advantage ◽  
Activating Mutations ◽  
Extracellular Signal

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

scholarly journals Antagonistic effects of activin A and TNF-α on the activation of L929 fibroblast cells via Smad3-independent signaling

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lingling Jiang ◽  
Boyang Liu ◽  
Yan Qi ◽  
Linru Zhu ◽  
Xueling Cui ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Activin A ◽  
Fibroblast Cells ◽  
L929 Cells ◽  
Tissue Fibrosis ◽  
Antagonistic Effects ◽  
Tnf Α ◽  
L929 Fibroblast ◽  
Relationship Of ◽  
Tgf Β1

AbstractFibroblasts play an important role in inflammation and tissue fibrosis. Both activin A and TNF-α can activate immune cells, however, the roles and relationship of them in activating fibroblasts in inflammation remain unclear. Here, this study revealed that TNF-α promoted the release of NO and IL-6 by L929 fibroblast cells, but co-treatment with activin A attenuated these effects. In contrast, activin A induced cell migration and increased the production of tissue fibrosis-related TGF-β1 and fibronectin, while TNF-α inhibited these function changes of L929 cells induced by activin A. Moreover, this study revealed that activin A and TNF-α regulated the activities of L929 cells via ERK1/2/MAPK pathway, rather than Smad3-dependent signaling pathway. Taken together, these data indicate that activin A and TNF-α exert mutually antagonistic effects on regulating fibroblasts activities, and the balance between their action may determine the process and outcome of fibroblasts-mediated inflammation.

scholarly journals Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

2012 ◽  
Vol 13 (12) ◽  
pp. 6217-6220 ◽  
Author(s):  
Hai-Zhou Shi ◽  
Peng Ren ◽  
Qing-Jun Lu ◽  
Marco Niedrgethmnn ◽  
Guo-Yang Wu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Polymorphisms ◽  
Tnf Α ◽  
Tgf Β1

scholarly journals Raf Kinase Inhibitor Protein Interacts with NF-κB-Inducing Kinase and TAK1 and Inhibits NF-κB Activation

2001 ◽  
Vol 21 (21) ◽  
pp. 7207-7217 ◽  
Author(s):  
Kam C. Yeung ◽  
David W. Rose ◽  
Amardeep S. Dhillon ◽  
Diane Yaros ◽  
Marcus Gustafsson ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Inhibitor Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitor Protein ◽  
Iκb Kinase ◽  
Tnf Α

ABSTRACT The Raf kinase inhibitor protein (RKIP) acts as a negative regulator of the mitogen-activated protein (MAP) kinase (MAPK) cascade initiated by Raf-1. RKIP inhibits the phosphorylation of MAP/extracellular signal-regulated kinase 1 (MEK1) by Raf-1 by disrupting the interaction between these two kinases. We show here that RKIP also antagonizes the signal transduction pathways that mediate the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to stimulation with tumor necrosis factor alpha (TNF-α) or interleukin 1 beta. Modulation of RKIP expression levels affected NF-κB signaling independent of the MAPK pathway. Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-κB pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-κB (IκB). In vitro kinase assays showed that RKIP antagonizes the activation of the IκB kinase (IKK) activity elicited by TNF-α. RKIP physically interacted with four kinases of the NF-κB activation pathway, NF-κB-inducing kinase, transforming growth factor beta-activated kinase 1, IKKα, and IKKβ. This mode of action bears striking similarities to the interactions of RKIP with Raf-1 and MEK1 in the MAPK pathway. Emerging data from diverse organisms suggest that RKIP and RKIP-related proteins represent a new and evolutionarily highly conserved family of protein kinase regulators. Since the MAPK and NF-κB pathways have physiologically distinct roles, the function of RKIP may be, in part, to coordinate the regulation of these pathways.

scholarly journals Grb2 binding induces phosphorylation-independent activation of Shp2

2019 ◽  
Author(s):  
Chi-Chuan Lin ◽  
Lukasz Wieteska ◽  
Kin Man Suen ◽  
Arnout Kalverda ◽  
Zamal Ahmed ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Tyrosine Phosphatase ◽  
Adaptor Protein ◽  
Cancer Cell Line ◽  
Mitogen Activated Protein Kinase ◽  
Activating Mutations ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Cancer Types

AbstractThe regulation of phosphatase activity is fundamental to the control of intracellular signalling and in particular the tyrosine kinase-mediated mitogen-activated protein kinase (MAPK) pathway. Shp2 is a ubiquitously expressed protein tyrosine phosphatase and its kinase-induced hyperactivity is associated with many cancer types. In non-stimulated cells we find that binding of the adaptor protein, Grb2, in its monomeric state initiates Shp2 activity independent of phosphatase phosphorylation. Grb2 forms a bidentate interaction with both the N-terminal SH2 and the catalytic domains of Shp2, releasing the phosphatase from its auto-inhibited conformation. Grb2 typically exists as a dimer in the cytoplasm. However, its monomeric state prevails under basal conditions when it is expressed at low concentration, or when it is constitutively phosphorylated on a specific tyrosine residue (Y160). Thus, Grb2 can activate Shp2 and downstream signal transduction, in the absence of extracellular growth factor stimulation or kinase-activating mutations, in response to defined cellular conditions. We identify a polypeptide biotool capable of blocking the Grb2-Shp2 interaction. This peptide down-regulates Shp2 activity in vitro and MAPK signalling in a cancer cell line.

scholarly journals Liver Resection Promotes (Regulates) Proinflammatory Cytokines in Patients with Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Farshid Fathi ◽  
Behnam Sanei ◽  
Mazdak Ganjalikhani Hakemi ◽  
Reza F. Saidi ◽  
Abbas Rezaei
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Resection ◽  
Liver Regeneration ◽  
Animal Studies ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Before And After ◽  
Tgf Β1

Background. Several animal studies have shown the roles of cytokines in regulating liver regeneration following liver resection (LR), which is a type of surgery designed to remove cancerous tumors from the liver. This study investigated how the expressions and serum levels of some pro- and anti-inflammatory cytokines in patients with hepatocellular carcinoma (HCC) were changed during LR. Methods. Liver tissues from 15 patients with HCC were collected and the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1 β, IL-10, and transforming growth factor-beta1 (TGF-β1) were assessed using real-time PCR assay at different times before and after LR. The serum values of TNF-α and IL-6 were also measured by ELISA. Results. After 60 and 90 minutes of LR, IL-6 gene expression was significantly increased P < 0.001 − 0.05 . The same trend was also observed in TNF-α expression after 90 minutes of LR P < 0.01 . No significant changes were observed in the expressions of IL-1α, IL-1β, IL-10, and TGF-β1 before and after LR. In addition, LR had significant effects on TNF-α and IL-6 serum levels P < 0.05 − 0.0001 . Conclusion. Our data provided further evidence to reveal that IL-6 and TNF-α cytokines are critical to improve liver regeneration.

scholarly journals Liver resection promotes (regulates) pro-inflammatory cytokines in patients with hepatocellular carcinoma

2021 ◽  
Author(s):  
Farshid Fathi ◽  
Behnam Sanei ◽  
Mazdak Ganjalikhani Hakemi ◽  
Reza F. Saidi ◽  
Abbass Rezaei
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Resection ◽  
Liver Regeneration ◽  
Inflammatory Cytokines ◽  
Animal Studies ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Tnf Α ◽  
Before And After ◽  
Tgf Β1

Abstract Objective: Several animal studies have shown the roles of cytokines in regulating liver regeneration following liver resection (LR), which is a type of surgery is designed to remove cancerous tumors from liver. This study investigated how the expressions and serum levels of some pro- and anti-inflammatory cytokines in patients with hepatocellular carcinoma (HCC) were changed during LR.Liver tissues from 15 patients with HCC were collected and the levels of interleukin-6 (IL-6), tumornecrosis factor-alpha (TNF-α), IL-1α, IL-1 β, IL-10, and transforming growth factor- beta1 (TGF-β1) were assessed using real-time PCR assay at different times before and after LR. The serum values of TNF-α and IL-6 were also measured by ELISA.Results: After 60 and 90 minutes of LR, IL-6 gene expression was significantly increased (P < 0.001-0.05). The same trend was also observed in TNF-α expression after 90 minutes of LR (P <0.01). No significant changes were observed in the expressions of IL-1α, IL-1β, IL-10, and TGF-β1 before and after LR. In addition, LR had significant effects on TNF-α and IL-6 serum levels (P<0.05-0.0001). Our data provided further evidence to reveal that IL-6 and TNF-α cytokines are critical to improve liver regeneration.

scholarly journals Crizotinib and Doxorubicin Cooperatively Reduces Drug Resistance by Mitigating MDR1 to Increase Hepatocellular Carcinoma Cells Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Shao ◽  
Run Shi ◽  
Zhen-Xing Gao ◽  
Shan-Shan Gao ◽  
Jing-Feng Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Kinase Inhibitor ◽  
Multiple Drug Resistance ◽  
Autophagic Cell Death ◽  
Multiple Drug ◽  
Parp 1

As the sixth most lethal cancers worldwide, hepatocellular carcinoma (HCC) has been treated with doxorubicin (Dox) for decades. However, chemotherapy resistance, especially for Dox is an even more prominent problem due to its high cardiotoxicity. To find a regimen to reduce Dox resistance, and identify the mechanisms behind it, we tried to identify combination of drugs that can overcome drug resistance by screening tyrosine kinase inhibitor(s) with Dox with various HCC cell lines in vitro and in vivo. We report here that combination of Crizo and Dox has a synergistic effect on inducing HCC cell death. Accordingly, Crizo plus Dox increases Dox accumulation in nucleus 3-16 times compared to Dox only; HCC cell death enhanced at least 50% in vitro and tumor weights reduced ranging from 35 to 65%. Combining these two drugs reduces multiple drug resistance 1 (MDR1) protein as a result of activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which phosphorylates eIF2α, leading to protein translational repression. Additionally, PERK stimulation activates C-Jun terminal kinase (JNK), resulting in accumulation of unfused autophagosome to enhance autophagic cell death via Poly-ADP-ribosyltransferase (PARP-1) cleavage. When the activity of PERK or JNK is blocked, unfused autophagosome is diminished, cleaved PARP-1 is reduced, and cell death is abated. Therefore, Crizo plus Dox sensitize HCC drug resistance by engaging PERK-p- eIF2α-MDR1, and kill HCC cells by engaging PERK-JNK- autophagic cell death pathways. These newly discovered mechanisms of Crizo plus Dox not only provide a potential treatment for HCC but also point to an approach to overcome MDR1 related drug resistance in other cancers.

TGF-β Receptor I Kinase Inhibitor Downregulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2355-2355
Author(s):  
Toshiaki Hayashi ◽  
Teru Hideshima ◽  
Klaus Podar ◽  
Paul Richardson ◽  
Olivier Munoz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Cell Growth ◽  
Kinase Inhibitor ◽  
Tumor Cell Growth ◽  
Β Receptor ◽  
And Migration ◽  
Tgf Β1

Abstract Transforming growth factors (TGFs) have pleiotropic biologic effects on tumor cells and their environment. In multiple myeloma (MM), we have reported that bone marrow stromal cells (BMSCs) from MM patients produce more TGF-β1 than BMSCs from healthy donors, which in turn induces interleukin-6 (IL-6) secretion. In this study, we delineate the functional squelae of TGF-β1 in MM, and importantly, show that the TGF-β receptor I kinase inhibitor SD-208 significantly decreases secretion of both IL-6 and vascular endothelial growth factor (VEGF) from BMSCs, as well as tumor cell growth triggered by MM cell adhesion to BMSCs. Cytokine production and MM cell proliferation triggered by TGF-β1 or adhesion to BMSCs were examined in the presence or absence of SD-208 using ELISA and 3H thymidine incorporation assay, respectively. Effects of SD-208 on TGF-β1-induced signaling pathways triggering IL-6 and VEGF transcription in BMSCs were delineated using immunofluorescence staining, immunoblotting and DNA-binding assay. We here show that adhesion of MM cells to BMSCs triggers secretion of TGF-β1, which further upregulates IL-6 and VEGF secretion in BMSCs. These cytokines in turn mediate MM cell growth, survival, drug resistance, and migration. Importantly, SD-208 significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-β1 or adhesion of MM cells to BMSCs. Moreover, SD-208 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. SD-208 works, at least in part, by blocking TGF-β1-triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1α, as well as related production of IL-6 and VEGF, respectively. These studies indicate that SD-208 inhibits production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of SD-208 to improve patient outcome in MM.

scholarly journals AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Eslam E. Abd El-Fattah ◽  
Sameh Saber ◽  
Mahmoud E. Youssef ◽  
Hanan Eissa ◽  
Eman El-Ahwany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Ki 67 ◽  
Tissue Invasion ◽  
Novel Approach ◽  
Promising Target ◽  
Tnf Α ◽  
Key Factor ◽  
Potential Basis ◽  
Α Level

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

Sign in / Sign up

Export Citation Format

Share Document