|
1
|
Size-Dependent Cytotoxic and Molecular Study of the Use of Gold Nanoparticles against Liver Cancer Cells. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12020901] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The size of nanomaterials influences physicochemical parameters, and variations in the size of nanomaterials can have a significant effect on their biological activities in cells. Due to the potential applicability of nanoparticles (NPs), the current work was designed to carry out a size-dependent study of gold nanoparticles (GNPs) in different dimensions, synthesized via a colloidal solution process. Three dissimilar-sized GNPs, GNPs-1 (10–15 nm), GNPs-2 (20–30 nm), and GNPs-3 (45 nm), were prepared and characterized via transmission electron microscopy (TEM), high-resolution TEM (HR-TEM), hydrodynamic size, zeta potential, and UV-visible spectroscopy, and applied against liver cancer (HepG2) cells. Various concentrations of GNPs (1, 2, 5, 10, 50, and 100 µg/mL) were applied against the HepG2 cancer cells to assess the percentage of cell viability via MTT and NRU assays; reactive oxygen species (ROS) generation was also used. ROS generation was increased by 194%, 164%, and 153% for GNPs-1, GNPs-2, and GNPs-3, respectively, in the HepG2 cells. The quantitative polymerase chain reaction (qPCR) data for the HepG2 cells showed up-regulation in gene expression of apoptotic genes (Bax, p53, and caspase-3) when exposed to the different-sized GNPs, and defined their respective roles. Based on the results, it was concluded that GNPs of different sizes have the potential to induce cancer cell death.
Collapse
|
|
2
|
Prawira A, Le TBU, Vu TC, Huynh H. Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma. Liver Int 2021; 41:608-620. [PMID: 33179425 PMCID: PMC7894323 DOI: 10.1111/liv.14728] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/14/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Infigratinib is a pan-FGFR (fibroblast growth factor receptor) inhibitor that has shown encouraging activity in FGFR-dependent hepatocellular carcinoma (HCC) models. However, long-term treatment results in the emergence of resistant colonies. We sought to understand the mechanisms behind infigratinib-induced tumour cell differentiation and resistance and to explore the potential of adding the CDK4/6 inhibitor ribociclib to prolong cell differentiation. METHODS Nine high and three low FGFR1-3-expressing HCC patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and subsequently treated with either infigratinib alone or in combination with ribociclib. Tumour tissues were then subjected to immunohistochemistry to assess cell differentiation, as indicated by the cytoplasmic-to-nuclear ratio and markers such as CYP3A4, HNF4α and albumin. Western blot analyses were performed to investigate the signalling pathways involved. RESULTS Infigratinib induced cell differentiation in FGFR1-3-dependent HCC PDX models, as indicated by an increase in the cytoplasmic/nuclear ratio and an increase in CYP3A4, HNF4α and albumin. Resistant colonies emerged in long-term treatment, characterised by a reversal of differentiated cell morphology, a reduction in the cytoplasmic-to-nuclear ratio and a loss of differentiation markers. Western blot analyses identified an increase in the CDK4/Cdc2/Rb pathway. The addition of ribociclib effectively blocked this pathway and reversed resistance to infigratinib, resulting in prolonged cell differentiation and growth inhibition. CONCLUSIONS Our findings demonstrate that the combined inhibition of FGFR/CDK4/6 pathways is highly effective in providing long-lasting tumour growth inhibition and cell differentiation and reducing drug resistance. Therefore, further clinical investigations in patients with FGFR1-3-dependant HCC are warranted.
Collapse
Affiliation(s)
- Aldo Prawira
- Laboratory of Molecular EndocrinologyDivision of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Thi Bich Uyen Le
- Laboratory of Molecular EndocrinologyDivision of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Thanh Chung Vu
- Laboratory of Molecular EndocrinologyDivision of Molecular and Cellular ResearchNational Cancer CentreSingapore
| | - Hung Huynh
- Laboratory of Molecular EndocrinologyDivision of Molecular and Cellular ResearchNational Cancer CentreSingapore
| |
Collapse
|
|
3
|
Evaluation of Apelin/APJ system expression in hepatocellular carcinoma as a function of clinical severity. Clin Exp Med 2020; 21:269-275. [DOI: 10.1007/s10238-020-00672-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022]
|
|
4
|
Lv S, Wang X, Bai X, Ning H, Li Y, Wen H, Lu W, Wang J. Mesenchymal epithelial transition factor regulates tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells through down-regulation of cyclin B1. Int J Biochem Cell Biol 2020; 128:105844. [PMID: 32882404 DOI: 10.1016/j.biocel.2020.105844] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 11/25/2022]
Abstract
Tumor necrosis factor-related apoptotic induction ligand can induce cell apoptosis in various tumor cells. However, many cancer cells are resistant to tumor necrosis factor-related apoptotic induction ligand. Therefore, overcoming the tumor necrosis factor-related apoptotic induction ligand resistance makes it possible for tumor necrosis factor-related apoptotic induction ligand-based anti-cancer therapies. In this study, we took mesenchymal epithelial transition factor as the research target to study its role in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma. Mesenchymal epithelial transition factor gene has been proved to be an effective predictor of recurrence after hepatocellular carcinoma resection. The expression of mesenchymal epithelial transition factor and cyclin B1 were measured in tumor necrosis factor-related apoptotic induction ligand-resistant and non-resistant hepatocellular carcinoma tissues. Cyclin B1-knockdown and cyclin B1-overexpression hepatocellular carcinoma cells were treated with tumor necrosis factor-related apoptotic induction ligand; mesenchymal epithelial transition factor knockout, mesenchymal epithelial transition factor re-introduction and cyclin B1 restored in hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand were established. And MTT, bromodeoxyuridine, flow cytometry and western blotting were performed to evaluate the effect of mesenchymal epithelial transition factor and cyclin B1 on hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand. In addition, subcutaneous tumor transplantation in nude mice was conducted to access the effect of mesenchymal epithelial transition factor and cyclin B1 on tumor formation in vivo. In conclusion, cyclin B1 enhanced the cell growth and inhibited apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells. And mesenchymal epithelial transition factor promoted the cell growth and apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells by regulating cyclin B1. Therefore, mesenchymal epithelial transition factor regulates the cyclin B1 to regulate tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells. Our results suggest a novel molecular mechanism for regulating tumor necrosis factor-related apoptotic induction ligand resistance, which might be helpful to select drug targets in the treatment of liver cancer.
Collapse
Affiliation(s)
- Shuai Lv
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China.
| | - Xijuan Wang
- Department of Pediatrics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan Province, China
| | - Xia Bai
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| | - Hanbing Ning
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| | - Yingxia Li
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| | - Hongtao Wen
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| | - Wenquan Lu
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| | - Jingyun Wang
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450018, Henan Province, China
| |
Collapse
|
|
5
|
Li D, Sun FF, Wang D, Wang T, Peng JJ, Feng JQ, Li H, Wang C, Zhou DJ, Luo H, Fu ZQ, Zhang T. Programmed Death Ligand-1 (PD-L1) Regulated by NRF-2/MicroRNA-1 Regulatory Axis Enhances Drug Resistance and Promotes Tumorigenic Properties in Sorafenib-Resistant Hepatoma Cells. Oncol Res 2020; 28:467-481. [PMID: 32560747 PMCID: PMC7751222 DOI: 10.3727/096504020x15925659763817] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.
Collapse
Affiliation(s)
- Dong Li
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Fei-Fan Sun
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Dan Wang
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Tao Wang
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Jing-Jing Peng
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Jian-Qiong Feng
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Hua Li
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Chao Wang
- Department of Pathology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Dai-Jun Zhou
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Hong Luo
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Zeng-Qiang Fu
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| | - Tao Zhang
- Department of Oncology, The General Hospital of Western Theater CommandChengduP.R. China
| |
Collapse
|
|
6
|
Xue C, Shao S, Yan Y, Yang S, Bai S, Wu Y, Zhang J, Liu R, Ma H, Chai L, Zhang X, Ren J. Association between G-protein coupled receptor 4 expression and microvessel density, clinicopathological characteristics and survival in hepatocellular carcinoma. Oncol Lett 2020; 19:2609-2620. [PMID: 32218811 PMCID: PMC7068660 DOI: 10.3892/ol.2020.11366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 06/14/2019] [Indexed: 12/27/2022] Open
Abstract
G-protein coupled receptor 4 (GPR4) acts as a proton-sensing receptor and plays a role in regulating angiogenesis. Endoglin/CD105 is a marker of cell proliferation in vascular endothelial cells, particularly in tumor vasculature cells. Although there have been several studies investigating angiogenesis in hepatocellular carcinoma (HCC), none have investigated the association between GPR4 and microvessel density (MVD)-CD105 in this type of cancer. In the present study, CD105 and GPR4 were found to be expressed in benign and malignant liver tissues by immunofluorescence staining and laser confocal microscopy. Compared with levels in benign tissues, CD105 and GPR4 were highly expressed in neoplastic tissues. Furthermore, the average fluorescence intensity of GPR4 and MVD-CD105 was positively correlated. GPR4 and CD105 were found to be co-localized in the vascular endothelium in tumor tissues. Furthermore, the expression of GPR4 was higher in the marginal region of tumor tissues compared with the central region. These findings suggest that the expression of GPR4 in tumor microvessels in HCC may be implicated in tumor angiogenesis and development. Furthermore, the association between the expression of GPR4 and the clinicopathological features of patients with HCC further suggests a role for GPR4 in tumor angiogenesis and growth. Overall, these results suggest the potential of GPR4 as a prognostic factor and as an antiangiogenic target in patients with HCC.
Collapse
Affiliation(s)
- Chaofan Xue
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuai Shao
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yanli Yan
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Si Yang
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuheng Bai
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yinying Wu
- Department of Chemotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jiangzhou Zhang
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Rui Liu
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Hailin Ma
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Linyan Chai
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaozhi Zhang
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Juan Ren
- Department of Radiotherapy, Oncology Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
7
|
Shi J, Zheng H, Yuan L. High NDRG3 expression facilitates HCC metastasis by promoting nuclear translocation of β-catenin. BMB Rep 2020. [PMID: 31072445 PMCID: PMC6675243 DOI: 10.5483/bmbrep.2019.52.7.201] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/β-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/β-catenin signaling and enhanced CSC-like properties were responsible for NDRG3- mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of β-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.
Collapse
Affiliation(s)
- JiKui Shi
- Department of Critical Care Medicine, Jining NO.1 People's Hospital, Jining 272011, P.R. China
| | - HongZhen Zheng
- Department of Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 200040, P.R. China
| | - LingYan Yuan
- Department of Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 200040, P.R. China
| |
Collapse
|
|
8
|
Kang X, Wang H, Li Y, Xiao Y, Zhao L, Zhang T, Zhou S, Zhou X, Li Y, Shou Z, Chen C, Li B. Alantolactone induces apoptosis through ROS-mediated AKT pathway and inhibition of PINK1-mediated mitophagy in human HepG2 cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1961-1970. [DOI: 10.1080/21691401.2019.1593854] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Xing Kang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Hijuan Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Yanwei Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Ying Xiao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Lili Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Tingting Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Shaohe Zhou
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Xiaolun Zhou
- Department of Pathogenic Biology, Gansu medical college, Pingliang, PR China
| | - Yi Li
- School of Computer Sciences, Xi’an Polytechnic University, Xi’an, PR China
| | - Zhexing Shou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Chao Chen
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| | - Bin Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, PR China
- College of Life Science, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi’an, PR China
| |
Collapse
|
|
9
|
Wu CH, Yang MY, Wang CJ. Quercetin-3-O-glucuronide inhibits doxorubicin resistance by reducing endoplasmic reticulum stress in hepatocellular carcinoma cells. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.01.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
|
|
10
|
Jin X, Cai L, Wang C, Deng X, Yi S, Lei Z, Xiao Q, Xu H, Luo H, Sun J. CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3. Cell Death Dis 2018; 9:318. [PMID: 29476051 PMCID: PMC5833678 DOI: 10.1038/s41419-018-0350-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/22/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies.
Collapse
Affiliation(s)
- Xiaoxin Jin
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Lifeng Cai
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Changfa Wang
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xiaofeng Deng
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Shengen Yi
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zhao Lei
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Qiangsheng Xiao
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Hongbo Xu
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Hongwu Luo
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Jichun Sun
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| |
Collapse
|
|
11
|
Wang Y, Wang Q, Song J. Inhibition of autophagy potentiates the proliferation inhibition activity of microRNA-7 in human hepatocellular carcinoma cells. Oncol Lett 2017; 14:3566-3572. [PMID: 28927113 PMCID: PMC5588049 DOI: 10.3892/ol.2017.6573] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 04/21/2017] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are important molecules that are able to regulate multiple cellular processes in cancer cells. miR-7 has been previously identified as a tumor suppressive miRNA in several types of cancer. The aim of the present study was to investigate whether miR-7 is able to regulate autophagy in hepatocellular carcinoma (HCC) cells. It was identified that miR-7 was significantly downregulated in tumor tissues compared with adjacent normal tissues. Overexpression of miR-7 inhibited cell proliferative activity, which was partially reversed by miR-7 inhibitor. In addition, overexpression of miR-7 significantly induced an increasen in autophagic activity, and luciferase activity assay and western blot analysis identified that mammalian target of rapamycin (mTOR) was a direct target of miR-7. In addition, inhibition of autophagy by 3-methyladenine resulted in a marked enhancement of the proliferation inhibition effect of miR-7. In conclusion, miR-7 was identified to induce proliferation inhibition and autophagy in HCC cells by targeting mTOR, and inhibition of autophagy may be utilized to enhance the antitumor activity of miR-7.
Collapse
Affiliation(s)
- Yanna Wang
- Department of Infectious Diseases, Yantai Hospital For Infectious Diseases, Yantai, Shandong 264001, P.R. China
| | - Qiaoling Wang
- Department of Infectious Diseases, Yantai Hospital For Infectious Diseases, Yantai, Shandong 264001, P.R. China
| | - Jiqing Song
- Nursing Department of Yantai Yeda Hospital, Yantai, Shandong 264006, P.R. China
| |
Collapse
|
|
12
|
Downregulation of paraoxonase 3 contributes to aggressive human hepatocellular carcinoma progression and associates with poor prognosis. Tumour Biol 2016; 37:14193-14203. [PMID: 27553024 DOI: 10.1007/s13277-016-5247-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 07/15/2016] [Indexed: 01/09/2023] Open
Abstract
Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC.
Collapse
|
|
13
|
Zhang Q, Lin Z, Yin X, Tang L, Luo H, Li H, Zhang Y, Luo W. In vitro and in vivo study of hydralazine, a potential anti-angiogenic agent. Eur J Pharmacol 2016; 779:138-46. [PMID: 26968484 DOI: 10.1016/j.ejphar.2016.03.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/08/2016] [Accepted: 03/08/2016] [Indexed: 02/05/2023]
Abstract
Hydralazine (HYD), an old routine clinical anti-hypertension drug, is rarely used in clinic nowadays. Since the strategy of repositioning old drugs was put forward, HYD has been reported to possess various biological activities, including antitumor efficacy and reducing intra-tumor microvessel. Here, we investigated that whether HYD had the ability of anti-angiogeneis and its underlying mechanism. Cells proliferation, wound-healing, Transwell migration and invasion, tube formation and rat aortic ring assays in vitro and chicken chorioallantoic membrane (CAM) model in vivo were designed to investigated HYD's anti-angiogenic effect. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed by enzyme-linked immune sorbent assay (ELISA). Hepatocellular carcinoma (HCC) mice model was used to evaluate HYD's effect on tumor growth and microvessel density. Our results showed that HYD not only inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, wound-healing, Transwell migration and invasion and tube formation, but also suppressed the microvessel outgrowth of rat aortic ring in vitro and the neovascularzation of CAM in vivo. Furthermore, we demonstrated that HYD attenuated tumor angiogenesis and tumor growth. In the co-culture system of Transwell migration, the secretion of VEGF and bFGF was reduced by HYD respectively. In sum, our data indicate that HYD has the pharmacological effect of ant-angiogenesis by interference with VEGF and bFGF signaling pathways in endothelial cells. These findings suggest that HYD might be a promising angiogenesis inhibitor and a potential effective therapeutic agent for cancer therapy.
Collapse
Affiliation(s)
- Quanwei Zhang
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Zhexuan Lin
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Xiukai Yin
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Lingzhi Tang
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Hongjun Luo
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Hui Li
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Yuan Zhang
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Wenhong Luo
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China.
| |
Collapse
|
|
14
|
Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis. Tumour Biol 2015; 37:5911-7. [PMID: 26592251 DOI: 10.1007/s13277-015-4443-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 11/13/2015] [Indexed: 12/13/2022] Open
Abstract
Betaine homocysteine methyltransferase (BHMT) catalyzes the synthesis of methionine using betaine and homocysteine (Hcy), which is restricted to the liver and kidney. Impaired BHMT pathway has been associated with hepatocellular carcinogenesis in Bhmt-/- mice model, and decreased BHMT was observed in a small sample of human hepatocellular carcinoma (HCC) patients. However, the prognostic significance of BHMT in HCC has not been elucidated. This study aimed to examine the expression of BHMT in HCC and investigate the relationship between its expression and prognosis of HCC patients. BHMT expression was analyzed in 68 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), 115 paraffin-embedded HCC sections (primary cohort), and 65 paraffin-embedded HCC sections (validation cohort) using immunohistochemistry (IHC). The results of IHC analysis showed that BHMT was decreased in tumorous tissues in 85.2 % (58/68) of cases compared to the corresponding adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased BHMT expression was closely correlated with serum α-fetoprotein (AFP) (p = 0.011), tumor size (p = 0.039), and vascular invasion (p = 0.017). Moreover, HCC patients with low BHMT expression had shorter overall survival (OS) and time to recurrence (TTR) than those with high BHMT expression in both primary cohort (p < 0.0001) and validation cohort (p < 0.05) assessed by the Kaplan-Meier method. In addition, multivariate analysis showed that BHMT was an independent prognostic factor for OS and TTR in the two cohorts (all p < 0.005). Collectively, our study demonstrated that BHMT could be served as a potential prognostic marker for HCC patients.
Collapse
|
|
15
|
He C, Dong X, Zhai B, Jiang X, Dong D, Li B, Jiang H, Xu S, Sun X. MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget 2015; 6:28867-28881. [PMID: 26311740 PMCID: PMC4745697 DOI: 10.18632/oncotarget.4814] [Citation(s) in RCA: 183] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/17/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.
Collapse
Affiliation(s)
- Changjun He
- Department of Surgery, the Affiliated Cancer Hospital of Harbin Medical University, Harbin, China
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuesong Dong
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bo Zhai
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xian Jiang
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Deli Dong
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China
| | - Baoxin Li
- Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China
| | - Hongchi Jiang
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shidong Xu
- Department of Surgery, the Affiliated Cancer Hospital of Harbin Medical University, Harbin, China
| | - Xueying Sun
- The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
16
|
Zhai B, Hu F, Yan H, Zhao D, Jin X, Fang T, Pan S, Sun X, Xu L. Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress. PLoS One 2015; 10:e0138485. [PMID: 26381511 PMCID: PMC4575108 DOI: 10.1371/journal.pone.0138485] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 08/31/2015] [Indexed: 12/17/2022] Open
Abstract
Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2α expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.
Collapse
Affiliation(s)
- Bo Zhai
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Fengli Hu
- Department of Gastroenterology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Haijiang Yan
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Dali Zhao
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xin Jin
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Taishi Fang
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shangha Pan
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xueying Sun
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lishan Xu
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| |
Collapse
|
|
17
|
Wang Y, Fukuda T, Isaji T, Lu J, Im S, Hang Q, Gu W, Hou S, Ohtsubo K, Gu J. Loss of α1,6-fucosyltransferase inhibits chemical-induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways. FASEB J 2015; 29:3217-27. [PMID: 25873065 DOI: 10.1096/fj.15-270710] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 03/31/2015] [Indexed: 12/28/2022]
Abstract
Up-regulation of core fucosylation catalyzed by α1,6-fucosyltransferase (Fut8) has been observed in hepatocellular carcinoma (HCC). Here, to explore the role of Fut8 expression in hepatocarcinogensis, we established the chemical-induced HCC models in the male wild-type (WT; Fut8(+/+)), hetero (Fut8(+/-)), and knockout (KO; Fut8(-/-)) mice by use of diethylnitrosamine (DEN) and pentobarbital (PB). In the Fut8(+/+) and Fut8(+/-) mice, multiple large and vascularized nodules were induced with an increased expression of Fut8 after DEN and PB treatment. However, the formation of HCC in Fut8(-/-) mice was suppressed almost completely. This potent inhibitory effect of Fut8 deficiency on tumorigenesis was also confirmed by the abolished tumor formation of Fut8 KO human hepatoma cell line cells by use of a xenograft tumor model. Furthermore, loss of the Fut8 gene resulted in attenuated responses to epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the HepG2 cell line, which provides the possible mechanisms for the contribution of Fut8 to hepatocarcinogensis. Taken together, our study clearly demonstrated that core fucosylation acts as a critical functional modulator in the liver and implicated Fut8 as a prognostic marker, as well as a novel, therapeutic target for HCC.
Collapse
Affiliation(s)
- Yuqin Wang
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Tomohiko Fukuda
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Tomoya Isaji
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Jishun Lu
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Sanghun Im
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Qinglei Hang
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Wei Gu
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Sicong Hou
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Kazuaki Ohtsubo
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| | - Jianguo Gu
- *Division of Regulatory Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan; and Department of Analytical Biochemistry, Faculty of Life Sciences, Kumamoto University, Japan
| |
Collapse
|
|
18
|
Zhai B, Jiang X, He C, Zhao D, Ma L, Xu L, Jiang H, Sun X. Arsenic trioxide potentiates the anti-cancer activities of sorafenib against hepatocellular carcinoma by inhibiting Akt activation. Tumour Biol 2015; 36:2323-2334. [PMID: 25416439 DOI: 10.1007/s13277-014-2839-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 11/11/2014] [Indexed: 01/05/2023] Open
Abstract
Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but it also induces the activation of Akt, which contributes to the mechanisms for the resistance to sorafenib. Arsenic trioxide (ATO) is a currently clinically used anticancer drug and displays its anticancer activities by inhibiting Akt activation. Therefore, we hypothesized that ATO may potentiate the anti-cancer activities of sorafenib against HCC. The results have demonstrated that ATO synergized with sorafenib to inhibit the proliferation and promote the apoptosis of HCC cells by diminishing the increased activation of Akt by sorafenib. ATO was shown to inhibit the expression or activation of Akt downstream factors, including glycogen synthase kinase (GSK)-3β, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which regulate cell apoptosis and were upregulated or activated by sorafenib. Both sorafenib and ATO downregulated the expression of cyclin D1, resulting in HCC cells arrested at G0/G1 phase. ATO downregulated the expression of Bcl-2 and Bcl-xL and upregulated the expression of Bax, indicating that ATO could induce the apoptosis of HCC cells through the intrinsic pathways; but sorafenib showed little effects on these proteins of Bcl-2 family. ATO synergized with sorafenib to suppress the growth of HCC tumors established in mice by inhibiting the proliferation and inducing the apoptosis of HCC cells in situ. These results indicate that ATO may be a potential agent that given in combination with sorafenib acts synergistically for treating HCC.
Collapse
Affiliation(s)
- Bo Zhai
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma. Hepatol Res 2015; 45:1-9. [PMID: 24533487 DOI: 10.1111/hepr.12310] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 01/27/2014] [Accepted: 02/03/2014] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor, and its vascularity is unique and greatly different from peripheral parenchyma of liver. Afferent and efferent vessels of HCC lesions come to differ as the lesion develops. The characteristic of the flow regulates the common style of metastasis. The portal tract of the HCC lesion is the first site of the intrahepatic metastasis, because cancer cells roll into the portal vein via efferent flow. On microscopic observation, HCC displays marked vascular abnormalities, arteriogenesis and capillarization. Arteriogenesis is defined as the growth of functional collateral arteries covered with smooth muscle cells from pre-existing arteries. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries. Several angiogenic factors have been reported, and some of them are studied as prognostic factors or target molecules of chemotherapeutic reagents. However, the mechanism of neovascularization during HCC development is still unclear. This review discusses the characteristics of angiogenesis in HCC and known angiogenic factors of HCC.
Collapse
Affiliation(s)
- Jun Muto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | | | | |
Collapse
|
|
20
|
Downregulation of MDR1 gene by cepharanthine hydrochloride is related to the activation of c-Jun/JNK in K562/ADR cells. BIOMED RESEARCH INTERNATIONAL 2014; 2014:164391. [PMID: 25386557 PMCID: PMC4216687 DOI: 10.1155/2014/164391] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 08/14/2014] [Accepted: 08/19/2014] [Indexed: 12/16/2022]
Abstract
The purpose of the study was to determine the signal transduction mechanism of cepharanthine hydrochloride (CH) on reversing tumor multidrug resistance. RT-PCR and Western blot analysis were used to determine the effects of CH on the expression of MDR1 mRNA and P-glycoprotein in K562/ADR cells when CH was used alone and combined with SP600125, a JNK inhibitor, to explore the effects of CH on JNK pathway. Western blot analysis was used to determine the effects of CH on c-Jun protein expression and phosphorylation, to explore the regulating effects of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins. Our results showed that the inhibitory effect of CH on MDR1 mRNA increased with the concentrations of CH (5.0, 10.0, and 20.0 μM) and the inhibitory effects of CH on MDR1 mRNA and P-glycoprotein increased with the incubation time of CH (0, 12, 24, 36, and 48 hours). The inhibitory effect was weakened after CH combined with SP600125. The expressions of c-Jun and p-c-Jun proteins increased with the incubation time of CH (0, 6, 12, and 24 hours). These findings suggest that CH downregulated the expressions of MDR1 mRNA and P-glycoprotein in a time and concentration manner; the mechanism may be mediated via activating c-Jun/JNK pathway.
Collapse
|
|
21
|
Lavi O, Skinner J, Gottesman MM. Network features suggest new hepatocellular carcinoma treatment strategies. BMC SYSTEMS BIOLOGY 2014; 8:88. [PMID: 25070212 PMCID: PMC4236726 DOI: 10.1186/s12918-014-0088-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/15/2014] [Indexed: 02/07/2023]
Abstract
Background Resistance to therapy remains a major cause of the failure of cancer treatment. A major challenge in cancer therapy is to design treatment strategies that circumvent the higher-level homeostatic functions of the robust cellular network that occurs in resistant cells. There is a lack of understanding of mechanisms responsible for the development of cancer and the basis of therapy-resistance mechanisms. Cellular signaling networks have an underlying architecture guided by universal principles. A robust system, such as cancer, has the fundamental ability to survive toxic anticancer drug treatments or a stressful environment mainly due to its mechanisms of redundancy. Consequently, inhibition of a single component/pathway would probably not constitute a successful cancer therapy. Results We developed a computational method to study the mechanisms of redundancy and to predict communications among the various pathways based on network theory, using data from gene expression profiles of hepatocellular carcinoma (HCC) of patients with poor and better prognosis cancers. Our results clearly indicate that immune system pathways tightly regulate most cancer pathways, and when those pathways are targeted by drugs, the network connectivity is dramatically changed. We examined the main HCC targeted treatments that are currently being evaluated in clinical trials. One prediction of our study is that Sorafenib combined with immune system treatments will be a more effective combination strategy than Sorafenib combined with any other targeted drugs. Conclusions We developed a computational framework to analyze gene expression data from HCC tumors with varying degrees of responsiveness and non-tumor samples, based on both Gene and Pathway Co-expression Networks. Our hypothesis is that redundancy is one of the major causes of drug resistance, and can be described as a function of the network structure and its properties. From this perspective, we believe that integration of the redundant variables could lead to the development of promising new methodologies to selectively identify and target the most significant resistance mechanisms of HCC. We describe three mechanisms of redundancy based on their levels of generalization and study the possible impact of those redundancy mechanisms on HCC treatments.
Collapse
|
|
22
|
Zhong J, Xiang B, Ma L, Li L. Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: A systematic review. Mol Clin Oncol 2014; 2:1091-1096. [PMID: 25279203 DOI: 10.3892/mco.2014.337] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 06/30/2014] [Indexed: 01/27/2023] Open
Abstract
The findings of randomized clinical trials (RCTs) regarding the efficacy of adjuvant conventional oral systemic chemotherapy (COSC) for patients with hepatocellular carcinoma (HCC) following curative hepatic resection (HR) are contradictory. Therefore, a systematic review of RCTs is required to evaluate the clinical efficacy of adjuvant COSC. Sources such as Medline, Embase and the Cochrane Library were systematically searched and all the RCTs comparing curative HR alone to HR plus COSC for HCC were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. No treatment-related mortality was reported by the included RCTs and the adverse effects of COSC were generally mild. However, adjuvant COSC did not achieve a statistically significant improvement in the 1-, 3- and 5-year overall survival (OR=1.43, 95% CI: 0.58-3.56, P=0.44; OR=1.39, 95% CI: 0.75-2.55, P=0.29; and OR=1.20, 95% CI: 0.46-3.16, P=0.71, respectively). In addition, adjuvant COSC did not achieve a statistically significant decrease in the incidence of 1-, 3- and 5-year tumor recurrence, with pooled ORs of 0.92 (95% CI: 0.26-1.35, P=0.66); 0.82 (95% CI: 0.66-1.01, P=0.06); and 0.84 (95% CI: 0.71-1.01, P=0.06), respectively. Narrative reviews offer no evidence supporting the use of COSC. Adjuvant COSC has provided marginal benefits for HCC patients following curative HR. Considering the efficacy of sorafenib for advanced HCC and the results of this systematic review, no further trials should be performed to assess the efficacy of adjuvant COSC.
Collapse
Affiliation(s)
- Jianhong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| |
Collapse
|
|
23
|
Zhai B, Hu F, Jiang X, Xu J, Zhao D, Liu B, Pan S, Dong X, Tan G, Wei Z, Qiao H, Jiang H, Sun X. Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther 2014; 13:1589-1598. [PMID: 24705351 DOI: 10.1158/1535-7163.mct-13-1043] [Citation(s) in RCA: 226] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but the acquired resistance to sorafenib results in limited benefits. Activation of Akt is thought to be responsible for mediating the acquired resistance to sorafenib. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance. Two sorafenib-resistant HCC cell lines, which had been established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure to sorafenib activated Akt via the feedback loop of mTOR but independent of protein phosphatase 2A in HCC cells. Autophagy participated in the resistance to sorafenib as inhibition of autophagy reduced the sensitivity of sorafenib-resistant HCC cells to sorafenib, whereas activation of autophagy by rapamycin had the opposite effect. However, rapamycin did not show a synergistic effect with sorafenib to inhibit cell proliferation, while it also activated Akt via a feedback mechanism in sorafenib-resistant HCC cells. Inhibition of Akt reversed the acquired resistance to sorafenib by switching autophagy from a cytoprotective role to a death-promoting mechanism in the sorafenib-resistant HCC cells. Akt inhibition by GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant feature in vivo. The results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC.
Collapse
Affiliation(s)
- Bo Zhai
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fengli Hu
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xian Jiang
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Xu
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dali Zhao
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Liu
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangha Pan
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuesong Dong
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Tan
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zheng Wei
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Haiquan Qiao
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongchi Jiang
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xueying Sun
- Authors' Affiliations: The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; and Departments of Gastroenterology and General Surgery, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
24
|
Zhao D, Zhai B, He C, Tan G, Jiang X, Pan S, Dong X, Wei Z, Ma L, Qiao H, Jiang H, Sun X. Upregulation of HIF-2α induced by sorafenib contributes to the resistance by activating the TGF-α/EGFR pathway in hepatocellular carcinoma cells. Cell Signal 2014; 26:1030-1039. [PMID: 24486412 DOI: 10.1016/j.cellsig.2014.01.026] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/05/2014] [Accepted: 01/22/2014] [Indexed: 12/16/2022]
Abstract
Sorafenib, the first-line systemic drug for advanced hepatocellular carcinoma (HCC), has demonstrated limited benefits with very low response rates. Thus it is essential to investigate the underlying mechanisms for the resistance to sorafenib and seek potential strategy to enhance its efficacy. Hypoxic cells inside solid tumors are extremely resistant to therapies as their survival ability is increased due to the cellular adaptive response to hypoxia, which is controlled by hypoxia-inducible factor (HIF)-1 and HIF-2. Sorafenib inhibits HIF-1α synthesis, making the hypoxic response switch from HIF-1α- to HIF-2α-dependent pathways and providing a mechanism for more aggressive growth of tumors. The present study has demonstrated that upregulation of HIF-2α induced by sorafenib contributes to the resistance of hypoxic HCC cells by activating the transforming growth factor (TGF)-α/epidermal growth factor receptor (EGFR) pathway. Blocking the TGF-α/EGFR pathway by gefitinib, a specific EGFR inhibitor, reduced the activation of STAT (signal transducer and activator of transcription) 3, AKT and ERK (extracellular signal-regulated kinase), and synergized with sorafenib to inhibit proliferation and induce apoptosis of hypoxic HCC cells. Transfection of HIF-2α siRNA into HCC cells downregulated the expression of VEGF (vascular endothelial growth factor), cyclin D1, HIF-2α and TGF-α, and inhibited the activation of EGFR. HIF-2α siRNA inhibited the proliferation and promoted the apoptosis of HCC cells in vitro, and synergized with sorafenib to suppress the growth of HCC tumors in vivo. The results indicate that targeting HIF-2α-mediated activation of the TGF-α/EGFR pathway warrants further investigation as a potential strategy to enhance the efficacy of sorafenib for treating HCC.
Collapse
Affiliation(s)
- Dali Zhao
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Bo Zhai
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Changjun He
- Department of Thoracic Surgery, The Third Affiliated Hospital, Harbin Medical University, Harbin 150040, China
| | - Gang Tan
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xian Jiang
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Shangha Pan
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xuesong Dong
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zheng Wei
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Lixin Ma
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Haiquan Qiao
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Hongchi Jiang
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Xueying Sun
- The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
| |
Collapse
|
|
25
|
Wang P, Sheng L, Wang G, Wang H, Huang X, Yan X, Yang X, Pei R. Association of transarterial chemoembolization with survival in patients with unresectable hepatocellular carcinoma. Mol Clin Oncol 2014; 2:203-206. [PMID: 24649333 DOI: 10.3892/mco.2014.239] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 12/20/2013] [Indexed: 01/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Only a minority of HCC patients benefit from curative therapies, such as surgical resection, liver transplantation, or percutaneous treatment, since the majority of HCCs are diagnosed at intermediate or advanced stages. To determine whether transarterial chemoembolization (TACE) affects survival in patients with unresectable HCC, we conducted a case-controlled study, investigating 129 patients diagnosed with intermediate- or advanced-stage HCC, classified according to the Barcelona Clinic Liver Cancer staging system. Of these 129 patients, 102 received TACE and 27 received symptomatic treatment alone. The primary follow-up endpoint was survival. The association of TACE with survival was estimated with the Kaplan-Meier method. Survival was significantly higher in the chemoembolization group compared to that in the symptomatic treatment group. The estimated 1-, 2- and 3-year survival rates were 61.8, 34.0 and 24.3% for the chemoembolization group and 51.9, 9.9 and 0% for the symptomatic treatment group (P<0.001). TACE was shown to significantly improve survival and is an effective form of treatment for patients with unresectable HCC.
Collapse
Affiliation(s)
- Peng Wang
- Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Lili Sheng
- Department of Medical Oncology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Guoxiang Wang
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Heping Wang
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Xinyu Huang
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Xiaoxing Yan
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Xiaohua Yang
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| | - Renguang Pei
- Department of Interventional Therapy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, P.R. China
| |
Collapse
|
|
26
|
Shaya FT, Breunig IM, Seal B, Mullins CD, Chirikov VV, Hanna N. Comparative and cost effectiveness of treatment modalities for hepatocellular carcinoma in SEER-Medicare. PHARMACOECONOMICS 2014; 32:63-74. [PMID: 24293197 DOI: 10.1007/s40273-013-0109-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
BACKGROUND The incidence of hepatocellular carcinoma (HCC) is increasing in the USA and worldwide. Several treatments are available for patients diagnosed at any disease stage. It remains unclear how medical expenditures vary across patients who remain untreated or undergo different modes of therapy. We evaluate the comparative and cost effectiveness of treatment modalities for HCC from a Medicare perspective. METHODS The Surveillance, Epidemiology, and End Results (SEER) registries and linked Medicare database with claims from Parts A/B were used to identify Medicare enrollees with initial diagnosis of HCC between 2000 and 2007 and followed through 2009. Patients were assigned to treatment modalities based on HCC staging systems: transplant, resection, liver directed, radiation, chemotherapy or no treatment. Survival benefits and cumulative Medicare expenditures were estimated in multivariate models, stratified by initial disease stage, to control for confounding. Cost-effectiveness ratios compared costs and benefits of the modalities across initial stages. RESULTS Cancer stages I, II, III, IV and unstaged represented 24, 9, 14, 17 and 37 % of 11,047 patients, respectively. Fewer than 40 % received any treatment. Relative to no treatment, transplant was most effective in reducing mortality, followed by resection, liver directed, and radiation or chemotherapy. Resection tended to be most cost effective in early staged and unstaged patients; transplant was least cost effective. In stage IV patients, liver directed therapy was more cost effective than chemotherapy or radiation. CONCLUSIONS Survival benefit was attributable to all treatment modalities. More effective treatments incurred greater Medicare expenditures, but resection patients incurred the least expenditures per year of life gained.
Collapse
Affiliation(s)
- Fadia T Shaya
- Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, 220 Arch Street, 12th floor, Baltimore, MD, 21201, USA,
| | | | | | | | | | | |
Collapse
|
|
27
|
Synthesis and antitumor activity evaluation of anilinoquinoline derivatives by the effect on the expression of polo-like kinase. Med Chem Res 2013. [DOI: 10.1007/s00044-013-0749-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
28
|
Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study. J Transl Med 2013; 11:192. [PMID: 23961994 PMCID: PMC3765954 DOI: 10.1186/1479-5876-11-192] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/16/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. METHODS The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action. RESULTS Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P < 0.05). The PDOX group had significantly higher WBC than the DOX group (P < 0.05), and higher PLT than Control (P < 0.05). Serum BUN and Cr levels were lower in the PDOX group than DOX and Control groups (P < 0.05). Compared with Control, DOX increased CK and CK-MB; while PDOX decreased CK compared with DOX (P < 0.05). Multiple spotty degenerative changes of the myocardium were observed in DOX-treated mice, but not in the Control and PDOX groups. PDOX could significantly reduce the Ki-67 positive rate of tumor cells, compared with DOX and Control groups. PDOX produced the effects at least via the ERK pathway. CONCLUSION Compared with DOX, PDOX may have better anti-metastatic efficacy and reduced side effects especially cardio-toxicities in this HCC model.
Collapse
|
|
29
|
Wang XP, Xu M, Gao HF, Zhao JF, Xu KC. Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma. World J Gastroenterol 2013; 19:2956-2962. [PMID: 23704829 PMCID: PMC3660821 DOI: 10.3748/wjg.v19.i19.2956] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 04/11/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect and tolerance of intraperitoneal perfusion of cytokine-induced killer (CIK) cells in combination with local radio frequency (RF) hyperthermia in patients with advanced primary hepatocellular carcinoma (HCC).
METHODS: Patients with advanced primary HCC were included in this study. CIK cells were perfused intraperitoneal twice a week, using 3.2 × 109 to 3.6 × 109 cells each session. Local RF hyperthermia was performed 2 h after intraperitoneal perfusion. Following an interval of one month, the next course of treatment was administered. Patients received treatment until disease progression. Tumor size, immune indices (CD3+, CD4+, CD3+CD8+, CD3+CD56+), alpha-fetoprotein (AFP) level, abdominal circumference and adverse events were recorded. Time to progression and overall survival (OS) were calculated.
RESULTS: From June 2010 to July 2011, 31 patients diagnosed with advanced primary HCC received intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia in our study. Patients received an average of 4.2 ± 0.6 treatment courses (range, 1-8 courses). Patients were followed up for 8.3 ± 0.7 mo (range, 2-12 mo). Following combination treatment, CD4+, CD3+CD8+ and CD3+CD56+ cells increased from 35.78% ± 3.51%, 24.61% ± 4.19% and 5.94% ± 0.87% to 45.83% ± 2.48% (P = 0.016), 39.67% ± 3.38% (P = 0.008) and 10.72% ± 0.67% (P = 0.001), respectively. AFP decreased from 167.67 ± 22.44 to 99.89 ± 22.05 ng/mL (P = 0.001) and abdominal circumference decreased from 97.50 ± 3.45 cm to 87.17 ± 4.40 cm (P = 0.002). The disease control rate was 67.7%. The most common adverse events were low fever and slight abdominal erubescence, which resolved without treatment. The median time to progression was 6.1 mo. The 3-, 6- and 9-mo and 1-year survival rates were 93.5%, 77.4%, 41.9% and 17.4%, respectively. The median OS was 8.5 mo.
CONCLUSION: Intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia is safe, can efficiently improve immunological status, and may prolong survival in HCC patients.
Collapse
MESH Headings
- Adult
- Biomarkers, Tumor/blood
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cells, Cultured
- Combined Modality Therapy
- Cytokine-Induced Killer Cells/immunology
- Cytokine-Induced Killer Cells/transplantation
- Disease Progression
- Female
- Humans
- Hyperthermia, Induced/adverse effects
- Immunotherapy, Adoptive/adverse effects
- Immunotherapy, Adoptive/methods
- Infusions, Parenteral
- Kaplan-Meier Estimate
- Liver Neoplasms/blood
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Male
- Middle Aged
- Time Factors
- Tomography, X-Ray Computed
- Treatment Outcome
- Tumor Burden
Collapse
|
|
30
|
Cheng JW, Lv Y. New progress of non-surgical treatments for hepatocellular carcinoma. Med Oncol 2013; 30:381. [PMID: 23292867 DOI: 10.1007/s12032-012-0381-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 12/11/2012] [Indexed: 02/07/2023]
Abstract
Many non-surgical treatments of hepatocellular carcinoma (HCC) have significantly improved in the last few decades and have shown survival benefits for selected patients with HCC. Today ablation can improve survival in individuals diagnosed in early HCC and even offer a curative treatment in selected candidates. Patients with intermediate-stage HCC benefit from transarterial chemoembolization (TACE). Drug-eluting bead transarterial chemoembolization (DEB-TACE) has shown a better combined ischemic and cytotoxic effect locally and less system toxicity when compared with conventional TACE. Those diagnosed at advanced stage benefit from sorafenib. In addition to TACE and sorafenib which could improve survival for selected patients, three-dimensional conformal radiotherapy treatment (3-DCRT), selection internal radiation therapy and systemic chemotherapy have also shown anti-tumor activity in the treatment of advanced HCC, but their survival benefit have not been proven. The limited effects of single therapy suggested that the combination would enhance the overall treatment effect. Other potential non-surgical therapies like gene therapy and immunotherapy are still in testing phases, except for some small-scale clinical trials which have been reported to show some beneficial effect. Here, we review the current non-surgical treatments in HCC and the new advances in this field.
Collapse
Affiliation(s)
- Ji-Wen Cheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an 710061, People's Republic of China.
| | | |
Collapse
|
|
31
|
Kim DY, Han KH. How to improve treatment outcomes for hepatocellular carcinoma of intermediate and advanced stage. Dig Dis 2012; 30:598-602. [PMID: 23258101 DOI: 10.1159/000343088] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma (HCC) consists of heterogeneous tumors regarding morphology, biology, and underlying liver function. In intermediate stage HCC, a high rate of recurrence and unsatisfactory treatment outcome after transarterial chemoembolization (TACE) are usually due to a large size and high number of tumors. TACE using drug-eluting beads has an advantage of a higher concentration of chemotherapeutic agent in the tumor. It might be applied to the patients with advanced diseases such as bilobar or recurrent HCC, and poor liver function. Blocking angiogenic stimuli after TACE would be a rational approach and radioembolization with (90)Y is a novel interventional modality for intermediate stage HCC. The modest anti-cancer effect of sorafenib coupled with an adverse event is a hurdle to overcome in advanced HCC. External radiotherapy has achieved promising results in HCC with portal vein invasion. The role of internal radiation therapy with (90)Y is not yet clear in advanced HCC. The safety and efficacy of hepatic arterial infusion chemotherapy have been reported in several studies. However, as in external radiotherapy, a well-designed randomized result is lacking. An appropriate combination strategy based on baseline patient and tumor characteristics may increase the survival of patients with intermediate or advanced HCC.
Collapse
Affiliation(s)
- Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | |
Collapse
|
|
32
|
Lee JY, Jung KH, Morgan MJ, Kang YR, Lee HS, Koo GB, Hong SS, Kwon SW, Kim YS. Sensitization of TRAIL-induced cell death by 20(S)-ginsenoside Rg3 via CHOP-mediated DR5 upregulation in human hepatocellular carcinoma cells. Mol Cancer Ther 2012; 12:274-85. [PMID: 23053497 DOI: 10.1158/1535-7163.mct-12-0054] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The TRAIL pathway is a potential therapeutic target for anticancer drugs due to selective cytotoxicity in cancer cells. Despite considerable promise, TRAIL or TRAIL receptor agonists have been used thus far with limited success in multiple clinical trials, in part due to acquired TRAIL resistance during chemotherapeutic treatment. Hepatocellular carcinoma (HCC) is a common solid tumor and the third leading cause of cancer-related death worldwide. Classical chemotherapy is not effective for HCC treatment and targeted therapy is limited to sorafenib. Isolated from Panax ginseng CA Meyer, 20(S)-ginsenoside Rg3 is a steroidal saponin with high pharmacologic activity that has been shown to sensitize cells to some chemotherapeutic agents. We investigated the sensitizing effect of Rg3 on TRAIL-induced cell death in HCC cells. We show Rg3 is capable of promoting TRAIL-induced apoptosis in a number of HCC cell lines, including HepG2, SK-Hep1, Huh-7, and Hep3B, but not in normal HL-7702 hepatocytes, indicating that Rg3 sensitization to TRAIL may be specific to cancer cells. Mechanistically, we found that Rg3 upregulates DR5 expression at the transcriptional level. DR5 upregulation in this case is mediated by C/EBP homology protein (CHOP), an important endoplasmic reticulum stress responsive protein. Furthermore, Rg3 is well tolerated and enhances the therapeutic efficacy of TRAIL in mouse xenograft models, suggesting that chemosensitization also occurs in vivo. Taken together, our study identifies Rg3 as a novel anticancer therapeutic agent and supports the further development of Rg3 as a chemosensitizer in combined therapy with TRAIL.
Collapse
Affiliation(s)
- Ju-Yeon Lee
- Institute for Medical Sciences, Ajou UniversitySchool of Medicine, Suwon, Seoul, Republic of Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Petralia G, Summers P, Viotti S, Montefrancesco R, Raimondi S, Bellomi M. Quantification of variability in breath-hold perfusion CT of hepatocellular carcinoma: a step toward clinical use. Radiology 2012; 265:448-56. [PMID: 22996748 DOI: 10.1148/radiol.12111232] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE To assess the variability of breath-hold perfusion computed tomography (CT) parameters and to investigate whether these measurements are affected by a commercial software upgrade in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS Written informed consent was obtained from all participants in this institutional ethics committee-approved study. Perfusion CT examinations in HCC patients were prospectively analyzed by three readers. Two readers repeated their analysis after an interval of at least 4 weeks. Inter- and intraobserver agreement, as well as intersoftware agreement, were assessed with intraclass correlation coefficients (ICCs) and Bland-Altman limits of agreement (LoA), with adjustment for correlation between repeated measures. RESULTS Ninety-three breath-hold perfusion CT examinations were included from 23 HCC patients. The ICC between readers was very high (>0.91) for blood flow (BF), high (>0.84) for blood volume (BV), and lower (>0.30 and >0.39) for mean transit time (MTT) and permeability surface area product (PS), respectively, while ICC between readings was high (>0.80) for BF and BV, good (>0.75) for PS, and lower (>0.38) for MTT, irrespective of software version. By using the current software, the clinically relevant percentage of LoA between readers for BF were -33%; for BV, -39%; for MTT, 55%; and for PS, -93%. Between readings by the most expert reader, the clinically relevant LoA were -35% for BF,-43% for BV, 33% for MTT, and -79% for PS. BF, BV, and PS values were significantly higher and MTT values were significantly lower (P<.01) with the current software version relative to the previous version. CONCLUSION With the current CT perfusion software, only decreases between scans of HCC lesions of more than 35% for BF and 43% for BV, or an increase of more than 55% for MTT, could be considered beyond the analysis variability. The perfusion parameters obtained with the current and previous software versions were not exchangeable. The results of this study are specific for breath-hold perfusion CT of HCC and may not apply to different acquisition protocols and tumors.
Collapse
Affiliation(s)
- Giuseppe Petralia
- Department of Radiology and Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
| | | | | | | | | | | |
Collapse
|
|
34
|
Zaydfudim V, Smoot RL, Clark CJ, Kendrick ML, Que FG, Farnell MB, Nagorney DM. Role of operative therapy in non-cirrhotic patients with metastatic hepatocellular carcinoma. J Gastrointest Surg 2012; 16:1516-23. [PMID: 22644447 DOI: 10.1007/s11605-012-1918-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 05/15/2012] [Indexed: 01/31/2023]
Abstract
INTRODUCTION We investigated the role of operative therapy in non-cirrhotic patients who developed metastatic hepatocellular carcinoma (HCC). METHODS This retrospective cohort study included consecutive non-cirrhotic patients with metastatic HCC after a prior hepatectomy treated between 1990 and 2009. Patients were stratified by operative therapy (resection, ablation, transcatheter therapy). Kaplan-Meier analyses with log-rank comparisons tested effects of operative therapy on overall survival (OS) and progression-free survival (PFS). RESULTS Of 195 non-cirrhotic patients treated for HCC during the study period, 98 [median age 65, interquartile range (IQR) 53-71; 55 % male] subsequently developed metastatic HCC (55 intrahepatic only). Median time to development of metastases after the index operation was 10 months (IQR 5-20 months); median number of metastases was 3 (IQR 2-7). Half of these patients (n = 50) underwent operative treatment of metastases; 20 (40 %) underwent metastasectomy, 18 (36 %) ablation, and 12 (24 %) transcatheter therapy. Operative therapy was associated with improved OS (p < 0.001). Resection or ablation was associated with improved PFS and OS compared to transcatheter therapy (all p ≤ 0.006). Nine patients (seven resection, two ablation) are disease free at a median of 50 months (IQR 24-80 months) posttreatment. CONCLUSIONS Resection and ablation are associated with an improved PFS and long-term OS and should be considered in select patients with metastatic HCC.
Collapse
Affiliation(s)
- Victor Zaydfudim
- Division of Gastroenterologic and General Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Liu Q, Li R, Zhu Z, Qian X, Guan W, Yu L, Yang M, Jiang X, Liu B. Enhanced antitumor efficacy, biodistribution and penetration of docetaxel-loaded biodegradable nanoparticles. Int J Pharm 2012; 430:350-8. [PMID: 22525076 DOI: 10.1016/j.ijpharm.2012.04.008] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 03/07/2012] [Accepted: 04/05/2012] [Indexed: 12/11/2022]
Abstract
To investigate the antitumor effect, biodistribution and penetration in tumors of docetaxel (DOC)-loaded polyethylene glycol-poly(caprolactone) (mPEG-PCL) nanoparticles on hepatic cancer model, DOC-loaded nanoparticles (DOC-NPs) were prepared with synthesized mPEG-PCL by nano-precipitated method with satisfactory encapsulation efficiency, loading capacity and size distribution. The fabricated nano-drugs were effectively transported into tumoral cells through endocytosis and localized around the nuclei in the cytoplasm. In vitro cytotoxicity test showed that DOC-NPs inhibited the murine hepatic carcinoma cell line H22 in a dose-dependent manner, which was similar to Taxotere, the commercialized formulation of docetaxel. The in vivo biodistribution performed on tumor-bearing mice by NIRF real-time imaging demonstrated that the nanoparticles achieved higher concentration and longer retention in tumors than in non-targeted organs after intravenous injection. The immunohistochemical analysis demonstrated that the nanoparticles located not only near the tumoral vasculatures, but also inside the tumoral interior. Therefore, DOC-NPs could penetrate into tumor parenchyma, leading to high intratumoral concentration of DOC. More importantly, the in vivo anti-tumor evaluation showed that DOC-NPs significantly inhibited tumor growth by tumor volume measurement and positron emission tomography and computed tomography (PET/CT) imaging observation. Taken together, the reported drug delivery system here could shed light on the future targeted therapy against hepatic carcinoma.
Collapse
Affiliation(s)
- Qin Liu
- The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, PR China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Zhou X, Yang J, Wang Y, Li W, Li-Ling J, Deng Y, Zhang M. Cucurbitacin B inhibits 12-O-tetradecanoylphorbol 13-acetate-induced invasion and migration of human hepatoma cells through inactivating mitogen-activated protein kinase and PI3K/Akt signal transduction pathways. Hepatol Res 2012; 42:401-11. [PMID: 22151918 DOI: 10.1111/j.1872-034x.2011.00933.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM Cucurbitacin B (CuB) is an active component isolated from various plants used as folk medicine in Asian countries and has shown diverse antitumor activities. There is, however, no documented effect of CuB on the migration and invasion of human hepatoma cells yet. The purpose of this study was to assess the effect of CuB on the migration and invasion of hepatoma cells and to explore the possible mechanism. METHODS Human hepatoma cell lines HepG2 and BEL-7402 were used for the study. Effects of CuB on cancer cell migration and invasion were evaluated in vitro with wound healing and transwell assays. The effect of CuB on the expression of matrix metalloproteinase (MMP)-9, mitogen-activated protein kinases (MAPKs), Akt, nuclear factor-κB (NF-κB), c-Fos and c-Jun was investigated with gelatin zymography and/or western blotting. RESULTS Cucurbitacin B has significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell invasion and migration in a concentration-dependent manner, which was accompanied with suppression of TPA-induced MMP-9 expression through inactivation of phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38 and Akt. In the nucleus, it has also strongly suppressed TPA-stimulated expression of NF-κB, c-Jun and c-Fos. CONCLUSION Cucurbitacin B has a potential value for suppressing metastasis of human hepatoma cells through suppressing the expression of MMP-9.
Collapse
Affiliation(s)
- Xueying Zhou
- Department of Clinical Pharmacology, China Medical University Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang Department of Pharmacy, General Hospital of Daqing Oilfield, Daqing Institute of Medical Genetics, School of Life Science & Key Laboratory for Bio-resources and Eco-environment of the Ministry of Education, Sichuan University, Chengdu, China
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Using rhodamine 123 accumulation in CD8 cells as a surrogate indicator to study the P-glycoprotein modulating effect of cepharanthine hydrochloride in vivo. J Biomed Biotechnol 2011; 2011:281651. [PMID: 21765632 PMCID: PMC3134191 DOI: 10.1155/2011/281651] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 03/16/2011] [Accepted: 04/28/2011] [Indexed: 12/27/2022] Open
Abstract
The purpose of this study was the use of rhodamine 123 (Rho123) accumulation in peripheral blood CD8(+)cells as a surrogate indicator to evaluate the modulating effect of P-glycoprotein (P-gp) inhibitors in the multidrug resistance (MDR) tumor-bearing mouse model. Rho123 was administered to mice, and the fluorescence level in CD8(+) cells was measured. Cepharanthine hydrochloride (CH) and verapamil (VER), two P-gp inhibitors, were administered to mice 1 hour prior to Rho123 administration in vivo or added to peripheral blood 1 hour prior to Rho123 addition ex vivo. The tumor inhibition effect of 5-fluorouracil/adriamycin/cisplatin (FAP) protocol plus CH was also investigated. A concentration- or dose-response relationship was shown between the concentration and dose of CH and Rho123 accumulation or the antitumor activity. In conclusion, the measurement of Rho123 accumulation in CD8(+) cells provides a surrogate assay for the screening of candidate P-gp inhibitors in preclinical trials, and CH is effective in modulating P-gp-mediated MDR in vivo.
Collapse
|
|
38
|
Wrzesinski SH, Taddei TH, Strazzabosco M. Systemic therapy in hepatocellular carcinoma. Clin Liver Dis 2011; 15:423-41, vii-x. [PMID: 21689622 PMCID: PMC3758582 DOI: 10.1016/j.cld.2011.03.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Many potential systemic therapies are being investigated for the treatment of hepatocellular carcinoma (HCC). The incidence of this malignancy is rising sharply and the vast majority of patients present at advanced stages. Although the earlier dismal results with cytotoxic chemotherapies made way for the development of locoregional therapies that provided improved overall survival, truly personalized therapy will require the selection of phenotypically similar stages of disease and populations, an understanding of the complex molecular and genetic pathways leading to HCC, and a keen understanding of the pathobiology of cirrhosis. Only then will we understand how to offer a particular patient at a specific stage of disease the appropriate therapy to truly prolong survival.
Collapse
Affiliation(s)
- Stephen H. Wrzesinski
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA,VA Connecticut Healthcare System, Comprehensive Cancer Center, 950 Campbell Avenue–111D, West Haven, CT 06516–2700, USA
| | - Tamar H. Taddei
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street/1080 LMP, PO Box 208019, New Haven, CT 06520–8019, USA,VA Connecticut Healthcare System, Hepatitis C Resource Center (HCRC), 950 Campbell Avenue-111H, West Haven, CT 06516-2700, USA
| | - Mario Strazzabosco
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street/1080 LMP, PO Box 208019, New Haven, CT 06520–8019, USA,Yale Liver Center, Department of Internal Medicine, Yale University, Cedar Street 333, New Haven, CT 06520, USA,Section of Digestive Diseases, University of Milan-Bicocca, Monza, Italy,Corresponding author. Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street/1080 LMP, PO Box 208019, New Haven, CT 06520-8019.
| |
Collapse
|
|
39
|
Zhang ZM, Guo JX, Zhang ZC, Jiang N, Zhang ZY, Pan LJ. Therapeutic options for intermediate-advanced hepatocellular carcinoma. World J Gastroenterol 2011; 17:1685-1689. [PMID: 21483627 PMCID: PMC3072631 DOI: 10.3748/wjg.v17.i13.1685] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Revised: 01/18/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies, ranking the sixth in the world, with 55% of cases occurring in China. Usually, patients with HCC did not present until the late stage of the disease, thus limiting their therapeutic options. Although surgical resection is a potentially curative modality for HCC, most patients with intermediate-advanced HCC are not suitable candidates. The current therapeutic modalities for intermediate-advanced HCC include: (1) surgical procedures, such as radical resection, palliative resection, intraoperative radiofrequency ablation or cryosurgical ablation, intraoperative hepatic artery and portal vein chemotherapeutic pump placement, two-stage hepatectomy and liver transplantation; (2) interventional treatment, such as transcatheter arterial chemoembolization, portal vein embolization and image-guided locoregional therapies; and (3) molecularly targeted therapies. So far, how to choose the therapeutic modalities remains controversial. Surgeons are faced with the challenge of providing the most appropriate treatment for patients with intermediate-advanced HCC. This review focuses on the optional therapeutic modalities for intermediate-advanced HCC.
Collapse
Affiliation(s)
- Zong-Ming Zhang
- Department of General Surgery, Digestive Medical Center, The First Affiliated Hospital, School of Medicine, Tsinghua University, Beijing 100016, China.
| | | | | | | | | | | |
Collapse
|
|
40
|
Peterson ML, Ma C, Spear BT. Zhx2 and Zbtb20: novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer. Semin Cancer Biol 2011; 21:21-7. [PMID: 21216289 PMCID: PMC3313486 DOI: 10.1016/j.semcancer.2011.01.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 12/22/2010] [Accepted: 01/04/2011] [Indexed: 12/21/2022]
Abstract
The mouse alpha-fetoprotein (AFP) gene is abundantly expressed in the fetal liver, normally silent in the adult liver but is frequently reactivated in hepatocellular carcinoma. The basis for AFP expression in the fetal liver has been studied extensively. However, the basis for AFP reactivation during hepatocarcinogenesis is not well understood. Two novel factors that control postnatal AFP repression, Zhx2 and Zbtb20, were recently identified. Here, we review the transcription factors that regulate AFP in the fetal liver, as well as Zhx2 and Zbtb20, and raise the possibility that the loss of these postnatal repressors may be involved in AFP reactivation in liver cancer.
Collapse
Affiliation(s)
- Martha L Peterson
- Department of Microbiology, Immunology & Molecular Genetics and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
| | | | | |
Collapse
|
|
41
|
Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by interferon-γ. Cytokine Growth Factor Rev 2011; 22:35-43. [PMID: 21334249 PMCID: PMC3068863 DOI: 10.1016/j.cytogfr.2011.01.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 12/17/2010] [Accepted: 01/06/2011] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-γ is a cytokine known for its immunomodulatory and anti-proliferative action. In the liver, IFN-γ can induce hepatocyte apoptosis or inhibit hepatocyte cell cycle progression. This article reviews recent mechanistic reports that describe how IFN-γ may direct the fate of hepatocytes either towards apoptosis or a cell cycle arrest. This review also describes a probable role for IFN-γ in modulating hepatocyte fate during liver regeneration, transplantation, hepatitis, fibrosis and hepatocellular carcinoma, and highlights promising areas of research that may lead to the development of IFN-γ as a therapy to enhance recovery from liver disease.
Collapse
Affiliation(s)
| | - Cheri L. Lamb
- Department of Biological Sciences, Boise State University
| | | |
Collapse
|
|
42
|
Pan JJ, Javle M, Thinn MM, Hsueh CT, Hsueh CT. Critical appraisal of the role of sorafenib in the management of hepatocellular carcinoma. Hepat Med 2010; 2:147-55. [PMID: 24367212 PMCID: PMC3846497 DOI: 10.2147/hmer.s7123] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Sorafenib is an oral multiple kinase inhibitor that blocks Raf, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. It has been approved in the US and Europe for the treatment of advanced hepatocellular carcinoma (HCC). Sorafenib has demonstrated a 44% increase in survival for advanced HCC patients, compared with best supportive care alone. We have reviewed the pharmacology, pivotal studies, and safety data for this agent. Sorafenib is the first systemic drug demonstrating a significant survival benefit, and is the standard of care for patients with advanced HCC for whom no potential curative option is available.
Collapse
Affiliation(s)
- Jen-Jung Pan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, TX, USA
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mie Mie Thinn
- Division of Oncology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | | | - Chung-Tsen Hsueh
- Division of Medical Oncology and Hematology, Loma Linda University Medical Center, Loma Linda, CA, USA
| |
Collapse
|
|
43
|
Affiliation(s)
- Timothy M Pawlik
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| |
Collapse
|