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Hepatocellular carcinoma mtor

Ying Liu, Yang Qi, Zhi-Hui Bai, Chen-Xu Ni, Qi-Hui Ren, Wei-Heng Xu, Jing Xu, Hong-Gang Hu, Lei Qiu, Jian-Zhong Li, Zhi-Gao He, Jun-Ping Zhang
AIM: Matrine is an alkaloid extracted from a Chinese herb Sophora flavescens Ait, which has shown chemopreventive potential against various cancers. In this study, we evaluated the anticancer efficacy of a novel derivative of matrine, (6aS, 10S, 11aR, 11bR, 11cS)-10- methylamino-dodecahydro- 3a,7a-diaza-benzo (de) (MASM), against human hepatocellular carcinoma (HCC) cells and their corresponding sphere cells in vitro and in vivo. METHODS: Human HCC cell lines (Hep3B and Huh7) were treated with MASM...
October 24, 2016: Acta Pharmacologica Sinica
Adam C Labonte, Sun-Sang J Sung, Lucas T Jennelle, Aditya P Dandekar, Young S Hahn
: The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Qi Zhang, Manyi Yang, Zhan Qu, Jixiang Zhou, Qin Jiang
Molecule-targeted therapy has become the research focus for hepatocellular carcinoma (HCC). Persistent PI3K-AKT activation is often detected in HCC, representing a valuable oncotarget for treatment. Here, we tested the anti-HCC activity by a potent AKT inhibitor: AKT inhibitor 1/2 (AKTi-1/2). In both established (HepG2 and Huh-7) and primary human HCC cells, treatment with AKTi-1/2 inhibited cell survival and proliferation, but induced cell apoptosis. AKTi-1/2 blocked AKT-mTOR activation, yet simultaneously provoked cytoprotective autophagy in HCC cells...
October 15, 2016: Biochemical and Biophysical Research Communications
Jinhyun Cho, Jeeyun Lee, Jusun Kim, Seung Tae Kim, Sujin Lee, Sun Young Kim, Sang Yun Ha, Cheol-Keun Park, Ho Yeong Lim
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus...
October 2016: Translational Oncology
Yu-Li Jia, Meng Xu, Chang-Wei Dou, Zhi-Kui Liu, Yu-Mo Xue, Bo-Wen Yao, Ling-Long Ding, Kang-Sheng Tu, Xin Zheng, Qing-Guang Liu
Aberrant autophagic processes have been found to have fundamental roles in the pathogenesis of different kinds of tumors, including hepatocellular carcinoma (HCC). P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), performs its function by acetylating both histone and non-histone proteins. Our previous studies showed that PCAF was downregulated in HCC tissues and its high expression was significantly associated with patient survival after surgery, serving as a prognostic marker. In this study we found that overexpression of PCAF induced autophagy of HCC cells and its knockdown depressed autophagy...
October 6, 2016: Cell Death & Disease
Rana Ahmed Youness, Hend Mohamed El-Tayebi, Reem Amr Assal, Karim Hosny, Gamal Esmat, Ahmed Ihab Abdelaziz
The insulin-like growth factor (IGF)-axis has been paradigmatically involved in hepatocellular carcinoma (HCC) tumor initiation, progression and drug resistance. Consequently, members of the IGF-axis and most importantly, IGF-1 receptor (IGF-1R) have been considered as intriguing targets for HCC therapy. Few miRNAs have been recently reported to be associated with IGF-1R regulation. The present study aimed to investigate the role of microRNA (miRNA/miR)-486-5p in the regulation of IGF-1R and its downstream signaling cascades...
October 2016: Oncology Letters
Diana I Sánchez, Bárbara González-Fernández, Beatriz San-Miguel, Juan Ortiz de Urbina, Irene Crespo, Javier González-Gallego, María J Tuñón
The sphingosine kinase (SphK)/sphingosine1-phosphate (S1P) pathway is involved in multiple biological processes, including carcinogenesis. Melatonin shows beneficial effects in cell and animal models of hepatocellular carcinoma (HCC), but it is unknown if they are associated with the modulation of the SphK/S1P system, along with different downstream signaling pathways modified in cancer. We investigated effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight i.p) once a week for 8 weeks...
October 1, 2016: Journal of Pineal Research
Ren-Jie Wei, Su-Shuan Lin, Wen-Ren Wu, Lih-Ren Chen, Chien-Feng Li, Han-De Chen, Chien-Ting Chou, Ya-Chun Chen, Shih-Shin Liang, Shang-Tao Chien, Yow-Ling Shiue
The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel anti-microtubule drug, ABT-751, in hepatocellular carcinoma-derived Huh-7 cells. Effects of ABT-751 were evaluated by immunocytochemistry, flow cytometric, alkaline comet, soft agar, immunoblotting, CytoID, green fluorescent protein-microtubule associated protein 1 light chain 3 beta detection, plasmid transfection, nuclear/cytosol fractionation, coimmunoprecipitation, quantitative reverse transcription-polymerase chain reaction, small-hairpin RNA interference and mitochondria/cytosol fractionation assays...
September 24, 2016: Toxicology and Applied Pharmacology
Wei Wang, Wen Bin Liu, Da Bing Huang, Wei Jia, Chu Shu Ji, Bing Hu
Drug resistance is one of the main hurdles for the successful treatment of hepatic carcinoma. However, the detailed mechanisms underlying resistance remain largely unknown and therapeutic approaches are limited. In the present study, we show that miR-122 confers resistance to 5-fluorouracil induced hepatocellular carcinoma cell apoptosis in vitro and reduces the potency of 5-fluorouracil in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-122 modulates drug resistance through down-regulation of expression of PCDH20, which belongs to the protocadherin gene family and negatively regulates Akt activation...
2016: American Journal of Cancer Research
Sora Kwon, Ji-Sook Jeon, Curie Ahn, Jung-Suk Sung, Inho Choi
Rapamycin, a specific inhibitor of mTOR used extensively as an immunosuppressant, has been expanded recently to cancer therapy, because the mTOR signal is known to be up-regulated in various cancer cells including hepatocellular carcinoma (HCC) cells. In spite of extensive efforts to employ mTOR inhibitors as anti-HCC therapy, they have not yet been approved by the FDA. Because of the heterogeneity and complexity of molecular signaling in HCC, suitable biomarkers should be identified or discovered to improve clinical efficacy of mTOR-specific inhibitors to HCC cells...
October 7, 2016: Biochemical and Biophysical Research Communications
Scott M Thompson, Matthew R Callstrom, Danielle E Jondal, Kim A Butters, Bruce E Knudsen, Jill L Anderson, Karen R Lien, Shari L Sutor, Ju-Seog Lee, Snorri S Thorgeirsson, Joseph P Grande, Lewis R Roberts, David A Woodrum
Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2-3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC)...
2016: PloS One
Haeseong Park, Ignacio Garrido-Laguna, Aung Naing, Siqing Fu, Gerald S Falchook, Sarina A Piha-Paul, Jennifer J Wheler, David S Hong, Apostolia M Tsimberidou, Vivek Subbiah, Ralph G Zinner, Ahmed O Kaseb, Shreyaskumar Patel, Michelle A Fanale, Vivianne M Velez-Bravo, Funda Meric-Bernstam, Razelle Kurzrock, Filip Janku
Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT...
August 31, 2016: Oncotarget
Hui-Chao Zhou, Jian-Hong Fang, Li-Ru Shang, Zi-Jun Zhang, Ye Sang, Li Xu, Yunfei Yuan, Min-Shan Chen, Limin Zheng, Yaojun Zhang, Shi-Mei Zhuang
We have previously shown that vessels that encapsulated tumour cluster (VETC), a prevalent vascular pattern in hepatocellular carcinoma (HCC), facilitates the entry of the whole tumour cluster into the bloodstream in an invasion-independent manner, and that angiopoietin 2 (Angpt2), the levels of which are increased in HCC cells, is essential for VETC formation. However, the mechanisms underlying VETC formation remains unclear. Herein, we characterized miR-125b and miR-100 as novel VETC suppressors by using human HCC specimens, and cell and animal models...
August 31, 2016: Journal of Pathology
Chuan Shen, Chenghong Peng, Baiyong Shen, Zhecheng Zhu, Ning Xu, Tao Li, Junjie Xie
Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM)...
August 25, 2016: Oncotarget
X Z Li, Y L Sun, L Q Cao, M J Li
The presented study aimed to investigate the antitumor efficacy of combination of oxaliplatin with rapamycin, an mTOR inhibitor, in hepatocellular carcinoma (HCC). The activation status of mTOR pathway was first examined in HCC cell lines HepG2, BEL7402, and HuH7 using Western blotting. Effects of rapamycin, oxaliplatin, and their combination on the proliferation of HCC cells were determined in vitro using MTT assay and in vivo using a nude mice model bearing HepG2 xenografts. Drug-induced cell apoptosis was examined by flow cytometry...
August 27, 2016: Neoplasma
Yasunari Nakamoto
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver...
August 25, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Alok R Singh, Shweta Joshi, Adam M Burgoyne, Jason K Sicklick, Sadakatsu Ikeda, Yuko Kono, Joseph R Garlich, Guillermo A Morales, Donald L Durden
Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI-3K/BRD4 inhibitors which can be used either alone or in combination with Sorafenib to treat patients with advanced HCC. Herein we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with Sorafenib inhibited proliferation, cell cycle, apoptosis and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep 3B, Hep G2, SK-Hep1 and Huh7 HCC cell lines...
August 5, 2016: Molecular Cancer Therapeutics
Aloísio Felipe-Silva, Alda Wakamatsu, Cinthya Dos Santos Cirqueira, Venâncio Avancini Ferreira Alves
AIM: To assess the distribution of proteins coded by genes reported as relevant for the molecular classification of hepatocellular carcinoma (HCC). METHODS: In this retrospective cross-sectional study, the following clinicopathological data were analyzed in 80 autopsied HCC patients: sex, age, ethnicity, alcohol intake, infection with hepatitis B and/or C virus, infection with human immunodeficiency virus, prior treatment, basic and immediate causes of death, liver weight, presence of cirrhosis, number and size of nodules, gross pattern, histological grade and variants, architectural pattern, invasion of large veins, and presence and location of extrahepatic metastases...
July 21, 2016: World Journal of Gastroenterology: WJG
Gang Zhao, Lei Dong, Haitao Shi, Hong Li, Xiaolan Lu, Xiaoyan Guo, Jinhai Wang
Fatty acid synthase (FASN) has emerged as a unique oncologic target for the treatment of cancers, including hepatocellular carcinoma (HCC). However, effective inhibitors of FASN for cancer treatment are lacking. MicroRNAs (miRNAs) have emerged as novel and endogenic inhibitors of gene expression. In the present study, we aimed to investigate the role of miR‑1207‑5p in HCC and the regulation of FASN through miR‑1207‑5p. The expression of miR-1207-5p was markedly reduced in HCC tissues and cell lines as detected with real‑time quantitative polymerase chain reaction (qPCR)...
September 2016: Oncology Reports
Jinsong Han, Ying Chen, Chao Yang, Ting Liu, Mingping Wang, Haojie Xu, Ling Zhang, Canhui Zheng, Yunlong Song, Ju Zhu
The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1...
October 21, 2016: European Journal of Medicinal Chemistry
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