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Hong Zhu, Dan-Dan Wang, Tao Yuan, Fang-Jie Yan, Chen-Ming Zeng, Xiao-Yang Dai, Zi-Bo Chen, Ying Chen, Tianyi Zhou, Guang-Han Fan, Meidan Ying, Ji Cao, Peihua Luo, Xi-Jie Liu, Yuandong Hu, Yong Peng, Qiaojun He, Bo Yang
Given that YAP signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling...
April 18, 2018: Cancer Research
Gen-Xia Liu, Shu Ma, Yao Li, Yan Yu, Yi-Xiang Zhou, Ya-Die Lu, Lin Jin, Zi-Lu Wang, Jin-Hua Yu
The putative tumor suppressor microRNA let-7c is extensively associated with the biological properties of cancer cells. However, the potential involvement of let-7c in the differentiation of mesenchymal stem cells has not been fully explored. In this study, we investigated the influence of hsa-let-7c (let-7c) on the proliferation and differentiation of human dental pulp-derived mesenchymal stem cells (DPMSCs) treated with insulin-like growth factor 1 (IGF-1) via flow cytometry, CCK-8 assays, alizarin red staining, real-time RT-PCR, and western blotting...
April 13, 2018: Experimental & Molecular Medicine
Wenya Zheng, Marie L Hemker, Mingyong Xie, Sebastian T Soukup, Patrick Diel
Isoflavones have been reported to stimulate muscle growth. The aim of this in vitro study was to examine anabolic activity and associated molecular mechanisms of a soy extract (SoyEx), isoflavone aglycones, and a mixture simulating the composition of SoyEx in C2C12 myotubes. C2C12 cells were differentiated into myotubes. The effects of SoyEx, genistein, daidzein, glycitein, and the mixture of genistein-daidzein-glycitein (Mix) on myotube diameter and number were determined. In addition, the expression of genes and proteins associated with anabolic activity was analyzed...
April 12, 2018: Planta Medica
Wenpeng Liu, Lei Kang, Juqiang Han, Yadong Wang, Chuan Shen, Zhifeng Yan, Yanhong Tai, Caiyan Zhao
Background: Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Materials and methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay...
2018: OncoTargets and Therapy
Yinan Zhao, An Liu, Yanyan Du, Yingnan Cao, Enxia Zhang, Quan Zhou, Hua Hai, Yuhong Zhen, Shubiao Zhang
Sucrose esters (SEs) have great potential applications in gene delivery because of their low toxicity, excellent biocompatibility, and biodegradability. By using tripeptide-based lipid (CDO) as a model lipid and SEs as helper lipids, a series of liposomes were prepared. The SEs with hydrophilic-lipophilic balance (HLB) values of 1, 6, 11, or 16 and the fatty acids of laurate, stearate, or oleate were used in the liposomes. We investigated the effect of HLB values of SEs and fatty acid types on gene transfection efficiency and toxicity of liposomes...
March 30, 2018: Acta Biomaterialia
Katerina Machackova, Martina Chrudinová, Jelena Radosavljevic, Pavlo Potalitsyn, Květoslava Křížková, Milan Fábry, Irena Selicharová, Michaela Collinsová, Andrzej Marek Brzozowski, Lenka Zakova, Jiri Jiracek
Insulin-like growth factors 1 and 2 (IGF-1 and -2) are protein hormones involved in normal growth and development, but also in lifespan regulation and cancer. They exert their functions mainly through the IGF-1R receptor, or by binding to the isoform A of insulin receptor (IR-A). The development of IGF-1 and IGF-2 antagonists is of great clinical interest. Mutations of A4 and A8 sites of human insulin lead to disproportionate effects on hormone IR binding and activation. Here, we systematically modified IGF-1 sites 45, 46 and 49 and IGF-2 sites 45 and 48, which correspond, or are close, to insulin A4 and A8 sites...
April 2, 2018: Biochemistry
Hany A Omar, Mai F Tolba
Benign prostate hypertrophy (BPH) is among the most common diseases with a huge impact on the quality of life of elderly men. There is a current need for the development of well-tolerated and effective preventive strategies to improve the clinical outcome. Caffeic acid phenethyl ester (CAPE) is an important active ingredient isolated from honey-bee propolis with potent anti-proliferative, anti-inflammatory and antioxidant effects. These properties promote CAPE as a promising candidate to be tested as an alternative therapy for BPH, which is still uninvestigated...
March 30, 2018: IUBMB Life
Yihui Chen, Wei Zhong, Baohua Chen, Chuanyu Yang, Song Zhou, Jing Liu
To investigate the anti-angiogenic effect and underlying molecular mechanisms of curcumin on HepG2 cells under hypoxic conditions, insulin-like growth factor 1 receptor (IGF-1R) knockout HepG2 cells were constructed using a clustered regularly interspaced short palindromic repeats/Cas9 genome-editing system. Hypoxic conditions were generated using cobalt chloride (CoCl2 ). An MTT assay was performed to measure the effects of curcumin on cell viability in hypoxia-induced IGF-1R knockout HepG2 cells, while western blot analysis was used to detect the expression of IGF-1R, phosphorylated (p)-protein kinase B (Akt), p-extracellular signal-regulated kinases (Erk)1/2, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF)...
March 2018: Experimental and Therapeutic Medicine
Senthiladipan Venkatachalam, Esther Mettler, Christian Fottner, Matthias Miederer, Bernd Kaina, Matthias M Weber
Background: Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes. Methods: To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant...
December 2017: Clinical and Translational Radiation Oncology
Malik Bisserier, Narendra Wajapeyee
Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. In this study, we used this information for identifying the mechanisms of resistance to Enhancer of Zeste Homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We discovered that EZH2 inhibitor resistance DLBCL cells showed activation of the IGF-1R, MEK, and PI3K pathways. Constitutive activation of IGF-1R, MEK or PI3K pathways were sufficient to confer resistance to EZH2 inhibitors in DLBCL...
March 23, 2018: Blood
Gordana Vlahovic, Kellen L Meadows, Ace J Hatch, Jingquan Jia, Andrew B Nixon, Hope E Uronis, Michael A Morse, M Angelica Selim, Jeffrey Crawford, Richard F Riedel, S Yousuf Zafar, Leigh A Howard, Margot O'Neill, Jennifer J Meadows, Sherri T Haley, Christy C Arrowood, Christel Rushing, Herbert Pang, Herbert I Hurwitz
PURPOSE: This study evaluated the maximum tolerated dose or recommended phase II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet regimen followed by the ganitumab, everolimus, and panitumumab triplet regimen. MATERIALS AND METHODS: This was a standard 3 + 3 dose escalation trial. Doublet therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to dose-limiting toxicities (DLTs). Panitumumab at 4...
March 23, 2018: Oncologist
Swadesh K Das, Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Devanand Sarkar, Luni Emdad, Paul B Fisher
Although prostate cancer (PCa) is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation associated gene-9 (syntenin, or syndecan binding protein (SDCBP)) in PCa progression. Using tissue samples from various Gleason stage PCa patients with adjacent normal tissue, a series of normal prostate and PCa cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in PCa invasion...
March 23, 2018: Cancer Research
Chung T Le, William P J Leenders, Remco J Molenaar, Cornelis J F van Noorden
The review discusses the effects of Epigallocatechin-3-gallate Gallate (EGCG) on glioma as a basis for future research on clinical application of EGCG. Epidemiological studies on the effects of green tea or EGCG on the risk of glioma is inconclusive due to the limited number of studies, the inclusion of all tea types in these studies, and the focus on caffeine rather than EGCG. In vivo experiments using EGCG monotherapy are inconclusive. Nevertheless, EGCG induces cell death, prevents cellular proliferation, and limits invasion in multiple glioma cell lines...
March 23, 2018: Nutrition and Cancer
Yu-Jen Chiu, Mann-Jen Hour, Yi-An Jin, Chi-Cheng Lu, Fuu-Jen Tsai, Tai-Lin Chen, Hsu Ma, Yu-Ning Juan, Jai-Sing Yang
Osteosarcoma is the most common primary malignancy of the bone and is characterized by local invasion and distant metastasis. Over the past 20 years, long-term outcomes have reached a plateau even with aggressive therapy. Overexpression of insulin-like growth factor 1 receptor (IGF‑1R) is associated with tumor proliferation, invasion and migration in osteosarcoma. In the present study, our group developed a novel quinazoline derivative, 6-fluoro‑2-(3-fluorophenyl)-4-(cyanoanilino)quinazoline (HMJ‑30), in order to disrupt IGF‑1R signaling and tumor invasiveness in osteosarcoma U‑2 OS cells...
March 16, 2018: International Journal of Oncology
Chunhong Zhang, Guomin Song, Weisheng Ye, Baoshan Xu
Osteosarcoma is one of the most frequent types of primary malignant bone neoplasm in children and adolescents. Despite advancements developed in therapeutic modalities, the 5-year overall survival rates for patients with metastatic osteosarcoma disease remain poor. The present study aimed to investigate the expression level of microRNA-302a (miR-302a) in osteosarcoma tissues and cell lines, and the biological roles of miR-302a in osteosarcoma cells. In addition, the molecular mechanism underlying its tumor suppressive roles was evaluated...
April 2018: Oncology Letters
L J Gu, Y Y Zhang, L Wang, J L Wang, X Wang, W J Yuan
Objective: To investigate the changes of insulin-like growth factor 1 (IGF-1) axis in chronic kidney disease (CKD) and its role in skeletal muscle atrophy. Methods: A total of 240 patients with CKD stage 1-5 (without dialysis treatment) were included between August 2016 and February 2017. Serum IGF-1 and IGF-1 binding protein-3 (IGFBP-3) were measured using chemiluminescence, and the influencing factors of serum IGF-1 and IGFBP-3 were analyzed. Besides, male Sprague-Dawley rats (200-250 g) were randomly assigned to the sham-operated control group (Control, n =15) and the 5/6 nephrectomy group ( n =15) as CKD animal model...
March 13, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Po-Chen Chu, Peng-Chan Lin, Hsing-Yu Wu, Kuen-Tyng Lin, Christina Wu, Tanios Bekaii-Saab, Yih-Jyh Lin, Chung-Ta Lee, Jeng-Chang Lee, Ching-Shih Chen
Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation...
March 21, 2018: Oncogene
Selma Cirrik, Geert W Schmid-Schönbein
Increased protease activity causes receptor dysfunction due to extracellular cleavage of different membrane receptors in hypertension. The vasodilatory effects of insulin-like growth factor-1 (IGF-1) are decreased in hypertension. Therefore, in the present study the association of an enhanced protease activity and IGF-1 receptor cleavage was investigated using the spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto (WKY) controls (n = 4). Matrix metalloproteinase (MMP) activities were determined using gelatin zymography on plasma and different tissue samples...
March 19, 2018: Hypertension Research: Official Journal of the Japanese Society of Hypertension
Steven A Rosenzweig
Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered...
2018: Advances in Cancer Research
Adam J Camblin, Emily A Pace, Sharlene Adams, Michael D Curley, Victoria Rimkunas, Lin Nie, Gege Tan, Troy Bloom, Sergio Iadevaia, Jason Baum, Charlene Minx, Akos Czibere, Chrystal U Louis, Daryl C Drummond, Ulrik B Nielsen, Birgit Schoeberl, J Marc Pipas, Robert M Straubinger, Vasileios Askoxylakis, Alexey A Lugovskoy
PURPOSE: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies...
March 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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