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Wei L, Wang Z, Jing N, Lu Y, Yang J, Xiao H, Guo H, Sun S, Li M, Zhao D, Li X, Qi W, Zhang Y. Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma. Chin Med 2022; 17:90. [PMID: 35907976 PMCID: PMC9338659 DOI: 10.1186/s13020-022-00645-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/20/2022] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC, accounting for 90% of primary liver cancer) was the sixth most common cancer in the world and the third leading cause of cancer death in 2020. The number of new HCC patients in China accounted for nearly half of that in the world. HCC was of occult and complex onset, with poor prognosis. Clinically, at least 15% of patients with HCC had strong side effects of interventional therapy (IT) and have poor sensitivity to chemotherapy and targeted therapy. Traditional Chinese medicine (TCM), as a multi-target adjuvant therapy, had been shown to play an active anti-tumor role in many previous studies. This review systematically summarized the role of TCM combined with clinically commonly used drugs for the treatment of HCC (including mitomycin C, cyclophosphamide, doxorubicin, 5-fluorouracil, sorafenib, etc.) in the past basic research, and summarized the efficacy of TCM combined with surgery, IT and conventional therapy (CT) in clinical research. It was found that TCM, as an adjuvant treatment, played many roles in the treatment of HCC, including enhancing the tumor inhibition, reducing toxic and side effects, improving chemosensitivity and prolonging survival time of patients. This review summarized the advantages of integrated traditional Chinese and modern medicine in the treatment of HCC and provides a theoretical basis for clinical research.
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Affiliation(s)
- Lai Wei
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Zeyu Wang
- Department of Scientific Research, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Niancai Jing
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Yi Lu
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Jili Yang
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Hongyu Xiao
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Huanyu Guo
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Shoukun Sun
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Mingjing Li
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China
| | - Wenxiu Qi
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China.
| | - Yue Zhang
- Department of Integrated Chinese and Western Medicine, Jilin Cancer Hospital, Changchun, 130000, Jilin, China.
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Bulutoglu B, Rey-Bedón C, Mert S, Tian L, Jang YY, Yarmush ML, Usta OB. A comparison of hepato-cellular in vitro platforms to study CYP3A4 induction. PLoS One 2020; 15:e0229106. [PMID: 32106230 PMCID: PMC7046200 DOI: 10.1371/journal.pone.0229106] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 01/29/2020] [Indexed: 02/06/2023] Open
Abstract
In vitro studies of drug toxicity and drug-drug interactions are crucial for drug development efforts. Currently, the utilization of primary human hepatocytes (PHHs) is the de facto standard for this purpose, due to their functional xenobiotic response and drug metabolizing CYP450 enzyme metabolism. However, PHHs are scarce, expensive, require laborious maintenance, and exhibit lot-to-lot heterogeneity. Alternative human in vitro platforms include hepatic cell lines, which are easy to access and maintain, and induced pluripotent stem cell (iPSC) derived hepatocytes. In this study, we provide a direct comparison of drug induced CYP3A4 and PXR expression levels of PHHs, hepatic cell lines Huh7 and HepG2, and iPSC derived hepatocyte like cells. Confluently cultured Huh7s exhibited an improved CYP3A4 expression and were inducible by up to 4.9-fold, and hepatocytes differentiated from human iPSCs displayed a 3.3-fold CYP3A4 induction. In addition, an increase in PXR expression levels was observed in both hepatic cell lines and iPSC derived hepatocytes upon rifampicin treatment, whereas a reproducible increase in PXR expression was not achieved in PHHs. Our results indicate that both hepatoma originated cell lines and iPSCs may provide alternative sources to primary hepatocytes, providing reliable and reproducible results for CYP3A4/PXR metabolism, upon in vitro maturation. This study may serve as a guide for the selection of suitable and feasible in vitro platforms for drug-drug interaction and toxicology studies.
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Affiliation(s)
- Beyza Bulutoglu
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Camilo Rey-Bedón
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Safak Mert
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, United States of America
| | - Lipeng Tian
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Yoon-Young Jang
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Martin L. Yarmush
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, United States of America
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - O. Berk Usta
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, United States of America
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Boscolo G, Jirillo A, Da Pian P. Complete Remission of Poorly Differentiated Squamous Liver Carcinoma after Systemic Chemotherapy and Surgery a Case Report. TUMORI JOURNAL 2019; 91:71-2. [PMID: 15850008 DOI: 10.1177/030089160509100113] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We report the case of a 64-year-old male patient diagnosed as having inoperable poorly differentiated liver carcinoma that could be completely resected after systemic chemotherapy with cisplatin and 5-fluorouracil.
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Affiliation(s)
- Giorgia Boscolo
- Division of Medical Oncology, Azienda Ospedaliera, Padua, Italy
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Zeidler JD, Fernandes-Siqueira LO, Carvalho AS, Cararo-Lopes E, Dias MH, Ketzer LA, Galina A, Da Poian AT. Short-term starvation is a strategy to unravel the cellular capacity of oxidizing specific exogenous/endogenous substrates in mitochondria. J Biol Chem 2017; 292:14176-14187. [PMID: 28663370 DOI: 10.1074/jbc.m117.786582] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 06/28/2017] [Indexed: 11/06/2022] Open
Abstract
Mitochondrial oxidation of nutrients is tightly regulated in response to the cellular environment and changes in energy demands. In vitro studies evaluating the mitochondrial capacity of oxidizing different substrates are important for understanding metabolic shifts in physiological adaptations and pathological conditions, but may be influenced by the nutrients present in the culture medium or by the utilization of endogenous stores. One such influence is exemplified by the Crabtree effect (the glucose-mediated inhibition of mitochondrial respiration) as most in vitro experiments are performed in glucose-containing media. Here, using high-resolution respirometry, we evaluated the oxidation of endogenous or exogenous substrates by cell lines harboring different metabolic profiles. We found that a 1-h deprivation of the main energetic nutrients is an appropriate strategy to abolish interference of endogenous or undesirable exogenous substrates with the cellular capacity of oxidizing specific substrates, namely glutamine, pyruvate, glucose, or palmitate, in mitochondria. This approach primed mitochondria to immediately increase their oxygen consumption after the addition of the exogenous nutrients. All starved cells could oxidize exogenous glutamine, whereas the capacity for oxidizing palmitate was limited to human hepatocarcinoma Huh7 cells and to C2C12 mouse myoblasts that differentiated into myotubes. In the presence of exogenous glucose, starvation decreased the Crabtree effect in Huh7 and C2C12 cells and abrogated it in mouse neuroblastoma N2A cells. Interestingly, the fact that the Crabtree effect was observed only for mitochondrial basal respiration but not for the maximum respiratory capacity suggests it is not caused by a direct effect on the electron transport system.
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Affiliation(s)
- Julianna D Zeidler
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil,.
| | - Lorena O Fernandes-Siqueira
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Ana S Carvalho
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Eduardo Cararo-Lopes
- Center of Toxins, Immune-Response and Cell Signaling, Instituto Butantan, São Paulo 05503-900, Brazil; Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, Brazil
| | - Matheus H Dias
- Center of Toxins, Immune-Response and Cell Signaling, Instituto Butantan, São Paulo 05503-900, Brazil
| | - Luisa A Ketzer
- Universidade Federal do Rio de Janeiro, Pólo de Xerém, Duque de Caxias 25245-390, Brazil
| | - Antonio Galina
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Andrea T Da Poian
- From the Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil,.
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DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway. Mol Cell Biochem 2014; 399:269-78. [PMID: 25348361 DOI: 10.1007/s11010-014-2253-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 10/17/2014] [Indexed: 12/22/2022]
Abstract
The aim of the present study was to investigate the effects of DNA-PKcs deficiency on the chemosensitivity of human hepatoma HepG2 cells to cisplatin (CDDP) and 5-fluorouracil (5-Fu), and to explore the underlying molecular mechanism. After transfection with DNA-PKcs siRNA or control siRNA, HepG2 cells were exposed to combination treatment of CDDP and 5-Fu. The cell viability, DNA damage, cell apoptosis, intracellular reactive oxygen species and glutathione (GSH) level, expression of apoptosis related proteins, activity of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and nuclear factor-κB (NF-κB) pathways were assessed. The combination of CDDP and 5-Fu had a synergistic cytotoxic effect in HepG2 cells in terms of the cell viability, DNA damage, apoptosis, and oxidative stress level. DNA-PKcs siRNA could sensitize the HepG2 cells to the combined treatment. DNA-PKcs suppression further reduced the Akt phosphorylation level and Bcl-2 expression in HepG2 cells exposed to CDDP and 5-Fu, but enhanced the expression of pro-apoptotic proteins p53 and caspase-3. Moreover, CDDP could inhibit the transcriptional activity of NF-κB through degradation of IkB-α, while 5-Fu alone seemed in some extent increases the NF-κB activity. The combined treatment with CDDP and 5-Fu resulted in significantly decrease of the transcriptional activity of NF-κB, which was further aggravated by DNA-PKcs siRNA treatment. In conclusion, DNA-PKcs suppression had complementary effects in combination with CDDP and 5-Fu treatment in HepG2 cells, which was associated with suppression of NF-κB signaling pathway cascade, activation of caspase-3 and p53, as well as down-regulation of Bcl-2 and GSH.
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Liu Y, Flynn TJ, Ferguson MS, Hoagland EM, Yu LL. Effects of dietary phenolics and botanical extracts on hepatotoxicity-related endpoints in human and rat hepatoma cells and statistical models for prediction of hepatotoxicity. Food Chem Toxicol 2011; 49:1820-7. [PMID: 21569817 DOI: 10.1016/j.fct.2011.04.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 04/22/2011] [Accepted: 04/27/2011] [Indexed: 01/15/2023]
Abstract
Toxicity assessment of botanical materials is difficult because they are typically complex mixtures of phytochemicals. In the present study, 16 phenolics were tested in both human (HepG2/C3A) and rat (MH1C1) hepatoma cells using a battery of eight toxicity endpoints. Cluster analysis was used to group the phenolics into four clusters for each cell type. Comparison of overall and individual liver activity of phenolics on both human and rat hepatoma cell lines showed significant differences for some endpoints. However, the cluster membership was similar across both cell types with the majority of phenolics clustering with the solvent control group (cluster 1). Each cell type produced a cluster of compounds with reported in vivo liver toxicity (cluster 2). Five herbal extracts were prepared and then tested as above. Using the cluster model developed with the phenolics, in the HepG2/C3A cells green tea was assigned to cluster 2 and the remaining four extracts to cluster 1. In the MH1C1 cells, green tea and thyme were assigned to cluster 2, cinnamon to cluster 4, and juniper berry and peppermint to cluster 1. The data suggest that this in vitro model may be useful for identifying hepatotoxic phenolics and botanical preparations rich in phenolics.
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Affiliation(s)
- Yitong Liu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742-7640, USA
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Kimura O, Takahashi T, Ishii N, Inoue Y, Ueno Y, Kogure T, Fukushima K, Shiina M, Yamagiwa Y, Kondo Y, Inoue J, Kakazu E, Iwasaki T, Kawagishi N, Shimosegawa T, Sugamura K. Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines. Cancer Sci 2010; 101:2145-2155. [PMID: 20707805 PMCID: PMC11159121 DOI: 10.1111/j.1349-7006.2010.01661.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM(+) subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM(-) subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/γc(null) (NOG) mice, revealed that a smaller number of EpCAM(+) cells (minimum 100) than EpCAM(-) cells was necessary for tumor formation. The bifurcated differentiation of EpCAM(+) cell clones into both EpCAM(+) and EpCAM(-) cells was obvious both in vitro and in vivo, but EpCAM(-) clones sustained their phenotype. These clonal analyses suggested that EpCAM(+) cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM(+) clones, but not into EpCAM(-) clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM(+) and EpCAM(-) cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM(+) population is biologically quite different from the EpCAM(-) population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC.
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Affiliation(s)
- Osamu Kimura
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Sivertsson L, Ek M, Darnell M, Edebert I, Ingelman-Sundberg M, Neve EPA. CYP3A4 catalytic activity is induced in confluent Huh7 hepatoma cells. Drug Metab Dispos 2010; 38:995-1002. [PMID: 20233841 DOI: 10.1124/dmd.110.032367] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Drug-induced hepatotoxicity is an important cause for disapproval, limitations of use, or withdrawal of drugs, and there is a high need for reproducible in vitro systems that can predict such toxicity. In this study, we show that confluent growth of the human hepatoma cell line Huh7 up to 5 weeks results in increased gene expression of several cytochromes P450 (P450s), UDP-glucuronosyltransferases, transporters, transcription factors, and several liver-specific genes, as measured by low-density array. The most striking effect was seen for CYP3A4 expression. Western blot analysis revealed increased amounts of CYP3A4 together with increased levels of NADPH-P450 reductase, cytochrome b(5), and albumin with prolonged time of confluence. By using the CYP3A4-specific substrates luciferin 6' benzyl ether, testosterone, and midazolam, we could confirm that the increased CYP3A4 gene expression also was accompanied by a similar increase in catalytic activity, inhibitable by the CYP3A4-selective inhibitor ketoconazole. The CYP3A4 activity in confluent cells was also inducible by rifampicin. Finally, the cell system could support the CYP3A4-dependent hepatotoxic activation of aflatoxin B(1), which was effectively inhibited by ketoconazole. Our results show that Huh7 cells grown confluent differentiate into a more metabolically competent cell line, especially with regard to CYP3A4.
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Affiliation(s)
- Louise Sivertsson
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Nanna Svartz väg 2, SE-171 77 Stockholm, Sweden.
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Lee JO, Lee KW, Oh DY, Kim JH, Im SA, Kim TY, Bang YJ. Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol 2009; 20:1402-1407. [PMID: 19502532 DOI: 10.1093/annonc/mdp010] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We evaluated the efficacy and toxicity of combination chemotherapy with capecitabine and cisplatin (XP) in patients with metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS From September 2003 to July 2007, we enrolled patients with HCC who had more than one measurable extrahepatic metastatic lesion. Patients received oral capecitabine (2000 mg/m(2)/day) with a schedule of 2 weeks on and 1 week off and cisplatin (60 mg/m(2)) on the first day of the 3-week cycle. RESULTS The study cohort consisted of 32 patients with a median age of 53 years. Overall response rate was 6.3% and disease control rate was 34.4%. The median time to progression (TTP) was 2.0 months [95% confidence interval (CI) 1.5-2.4] and the median overall survival (OS) time was 12.2 months (95% CI 6.5-17.8). The grade 3/4 hematologic toxic effects included thrombocytopenia (7.6%), neutropenia (4.3%) and anemia (2.1%). The grade 3/4 non-hematologic toxic effects included elevated hepatic aminotransferase (12.9%), jaundice (3.2%), mucositis (3.2%) and nausea (3.2%). There was no treatment-related mortality. CONCLUSIONS Based on the observed response rate and TTP, XP combination chemotherapy showed modest antitumor efficacy in patients with metastatic HCC as systemic first-line treatment. However, XP combination chemotherapy showed tolerable toxicity and demonstrated favorable OS time.
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Affiliation(s)
- J O Lee
- Department of Internal Medicine, Seoul National University Hospital, Chongno-gu, Seoul, Korea
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Choi S, Sainz B, Corcoran P, Uprichard S, Jeong H. Characterization of increased drug metabolism activity in dimethyl sulfoxide (DMSO)-treated Huh7 hepatoma cells. Xenobiotica 2009; 39:205-17. [PMID: 19280519 DOI: 10.1080/00498250802613620] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The objective of this study was to characterize Huh7 cells' baseline capacity to metabolize drugs and to investigate whether the drug metabolism was enhanced upon treatment with dimethyl sulfoxide (DMSO). The messenger RNA (mRNA) levels of major Phase I and Phase II enzymes were determined by quantitative real-time-polymerase chain reaction (RT-PCR), and activities of major drug-metabolizing enzymes were examined using probe drugs by analysing relevant metabolite production rates. The expression levels of drug-metabolizing enzymes in control Huh7 cells were generally very low, but DMSO treatment dramatically increased the mRNA levels of most drug-metabolizing enzymes as well as other liver-specific proteins. Importantly, functionality assays confirmed concomitant increases in drug-metabolizing enzyme activity. Additionally, treatment of the Huh7 cells with 3-methylcholanthrene induced cytochrome P450 (CYP) 1A1 expression. The results indicate that DMSO treatment of Huh7 cells profoundly enhances their differentiation state, thus improving the usefulness of this common cell line as an in vitro hepatocyte model.
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Affiliation(s)
- S Choi
- Center for Pharmaceutical Biotechnology,University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, USA
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Lee JO, Kim DY, Lim JH, Seo MD, Yi HG, Oh DY, Im SA, Kim TY, Bang YJ. Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation. J Gastroenterol Hepatol 2009; 24:800-805. [PMID: 19175825 DOI: 10.1111/j.1440-1746.2008.05672.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The majority of patients with post-transplantation recurrence of hepatocellular carcinoma (HCC) have extrahepatic metastases and multifocal lesions. Therefore, they have few treatment options and may not be amenable for local therapy. The safety and efficacy of palliative chemotherapy in this population has not been reported. METHODS We retrospectively analyzed 24 patients who received palliative chemotherapy for recurrent HCC after liver transplantation between January 2000 and December 2006 at the Seoul National University Hospital. RESULTS The mean age of patients was 55 years (range 42-70 years). The most commonly used chemotherapeutic regimens were 5-fluorouracil (5-FU)/cisplatin (n = 9), which was followed by capecitabine/cisplatin (n = 4), 5-FU/mitomycin (n = 3), 5-FU/oxaliplatin (n = 1), S-1 (n = 1), capecitabine (n = 1), gemcitabine/oxaliplatin (n = 1), gemcitabine/cisplatin (n = 1), 5-FU/interferon (n = 1) and sorafenib (n = 2). The Grade 3/4 hematological toxicity was neutropenia (29.1%), thrombocytopenia (20.9%) and anemia (20.9%). There were no cases of neutropenic fever or bleeding events. The Grade 3/4 non-hematological toxicity included elevation of liver transaminase (8.4%) and jaundice (16.7%). No patient showed an objective response and four patients (16.7%) demonstrated stable disease. The median time to progression was 7.0 weeks (95% CI 5.8-8.2) and the median overall survival was 16.6 weeks (95% CI 10.1-23.1). CONCLUSION Palliative chemotherapy can be delivered to patients with recurrent HCC after liver transplantation with tolerable toxicity. However, the efficacy to date is not satisfactory. Therefore, more effective systemic chemotherapy is needed for this group of patients.
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Affiliation(s)
- Jeong-Ok Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
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Kogure T, Ueno Y, Kimura O, Kondo Y, Inoue J, Fukushima K, Iwasaki T, Shimosegawa T. A novel third generation bisphosphonate, minodronate (YM529), prevented proliferation and migration of hepatocellular carcinoma cells through inhibition of mevalonate pathway. Hepatol Res 2009; 39:479-489. [PMID: 19207585 DOI: 10.1111/j.1872-034x.2008.00484.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
AIM Skeletal metastases and bone metasitasis are a common occurrence in patients with advanced hepatocellular carcinoma (HCC). Bisphosphonates (BPs), which are used for the treatment of osteoporosis and tumor-associated hypercalcemia, have recently been reported to decrease skeletal morbidity in patients with metastatic bone disease. Several studies revealed that nitrogen-containing BPs (N-BPs) could inhibit tumor growth and migration, indicating the possibility that N-BPs have direct inhibitory effects. We aimed to determine the effects of novel a N-BP (YM529) on human HCC cells in vitro. METHODS HCC cells were treated with various concentrations of YM529 and the growth inhibition rate was determined. Apoptosis was evaluated by caspase-3/7 assay and caspase-9 cleavage detection. The effects of YM529 on the migration of HCC cells induced by hepatocyte growth factor (HGF) were determined by cell migration assay. To evaluate the involvement of the mevalonate pathway, farnesol (FOH) and geranylgeraniol (GGOH) were added. RESULTS YM529 inhibited the proliferation of HCC cells in a dose-dependent manner. The activation of caspase-3/7 and cleavage of caspase-9 demonstrated the involvement of apoptosis in cytotoxicity. GGOH reduced the growth inhibitory effect of YM529 and suppressed the induction of caspase-3/7 activities by YM529 on HCC cells. YM529 inhibited tumor cell migration induced by HGF and this effect was reduced by co-treatment with GGOH. CONCLUSION YM529 inhibited the cell proliferation and migration of HCC cells, implicating the involvement of the mevalonate pathway. These results suggest that N-BPs are potential agents for the treatment of HCC skeletal metastases.
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Affiliation(s)
- Takayuki Kogure
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan
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Katamura Y, Aikata H, Kimura Y, Azakami T, Kawaoka T, Takaki S, Waki K, Hiramatsu A, Kawakami Y, Takahashi S, Chayama K. Successful treatment of pulmonary metastases associated with advanced hepatocellular carcinoma by systemic 5-fluorouracil combined with interferon-alpha in a hemodialysis patient. Hepatol Res 2009; 39:415-20. [PMID: 19178587 DOI: 10.1111/j.1872-034x.2008.00448.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A 54-year-old man maintained on hemodialysis had a relapse of multiple pulmonary metastases after multimodal therapy for primary hepatocellular carcinoma (HCC). He was treated with tegafur-uracil (UFT; 400 mg/day) and interferon alfa (IFN-alpha; 5 x 10(6) units three times per week) for 4 weeks. Following this he was treated with systemic 5-fluorouracil (5-FU; 1000 mg/day, 5 days per week) and cisplatin (CDDP; 10 mg/day, 5 days per week for 2 weeks). The response to the above treatments was inadequate; pulmonary metastasis deteriorated. Finally, we selected systemic chemotherapy of 5-FU (750 mg/day, 5 days per week) and recombinant IFN-alpha-2b (3 x 10(6) units three times per week) for 2 weeks. This therapy resulted in excellent shrinkage of pulmonary metastases, without severe adverse reactions. Hemodialysis was performed three times a week. We report a case of successful treatment of pulmonary metastases by systemic combination chemotherapy of 5-FU-IFN, previously unsuccessfully treated with UFT-IFN and 5-FU-CDDP in a patient on hemodialysis. Further studies are needed to select appropriate drugs with fluoropyrimidine-based systemic chemotherapy, and to analyze the pharmacokinetics of those agents in hemodialysis patients with HCC and extrahepatic metastases.
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Affiliation(s)
- Yoshio Katamura
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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The effect of targeted magnetic nanopaticles on hepatoma and the expression of bcl-2/bax protein. ACTA ACUST UNITED AC 2008; 28:443-6. [PMID: 18704308 DOI: 10.1007/s11596-008-0415-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Indexed: 01/31/2023]
Abstract
The effect of targeted magnetic nanoparticles on hepatoma and the underlying mechanism were examined. Nude mice transplanted with a human hepatoma cell line (HepG2 cells) were randomized into 5 groups, including: (1) group A, receiving normal saline, (2) group B, receiving 5-fluorouracil (5-Fu), (3) group C, receiving magnetic nanoparticles containing 5-Fu, (4) group D, consisting of treatment with magnetic nanoparticles containing 5-Fu and inside magnetic field and (5) group E, receiving pure magnetic nanoparticles and inside magnetic field. Morphological features of transplanted tumors in mice in each group were observed under transmission electron microscope (TEM). The expression of bcl-2/bax protein was immunohistochemically detected by SABC method. The results showed that a large number of apoptotic tumor cells were found in group B and group D under TEM. The expression of bcl-2 protein was significantly decreased and the expression of bax protein increased significantly in both group B and D as compared with those in group A, C and E (P<0.01 for all). The decrease in bcl-2 and the increase in bax were more in group D as compared with group B (P<0.01). It is concluded that the targeted magnetic nanoparticles containing 5-Fu can improve the chemotherapeutic effect of 5-Fu by decreasing bcl-2 expression, increasing bax expression and inducing apoptosis of the liver cancer cells.
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Chemotherapy with etoposide, doxorubicin, cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma. Med Oncol 2007; 25:201-6. [DOI: 10.1007/s12032-007-9013-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Accepted: 09/19/2007] [Indexed: 12/11/2022]
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Wang JM, Xiao BL, Zheng JW, Chen HB, Zou SQ. Effect of targeted magnetic nanoparticles containing 5-FU on expression of bcl-2, bax and caspase 3 in nude mice with transplanted human liver cancer. World J Gastroenterol 2007; 13:3171-5. [PMID: 17589894 PMCID: PMC4436601 DOI: 10.3748/wjg.v13.i23.3171] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the anti-tumor effect and mechanisms of magnetic nanoparticles targeting hepatocellular carcinoma.
METHODS: Human hepatocellular carcinoma was induced in nude mice, and the mice were randomly divided into group A receiving normal saline, group B receiving magnetic nanoparticles containing 5-fluorouracil (5-FU), group C receiving 5-FU, and group D receiving magnetic nanoparticles containing 5-FU with a magnetic field built in tumor tissues. The tumor volume was measured on the day before treatment and 1, 4, 7, 10 and 13 d after treatment. Tumor tissues were isolated for examination of the expression of bcl-2, bax and caspase 3 by immunohistochemical method, reverse transcription polymerase chain reaction and Western blotting.
RESULTS: The tumor volume was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P < 0.01). The volume was markedly lower in group D than in group C (P < 0.05). The expression of protein and mRNA of bcl-2 was markedly lower in groups C and D than in groups A and B (group C or D vs group A or B, P < 0.01), and was markedly lower in group D than in group C (P < 0.01). The expression of bax and caspase 3 in groups C and D was significantly increased, compared with that in groups A and B (P < 0.01).
CONCLUSION: The targeted magnetic nanoparticles containing 5-FU can improve the chemotherapeutic effect of 5-FU against hepatocellular carcinoma by decreasing the expression of bcl-2 gene, and increasing the expression of bax and caspase 3 genes.
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Affiliation(s)
- Jian-Ming Wang
- Department of General Surgery of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hangkong Road, Wuhan 430030, Hubei Province, China.
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Emond JC, Samstein B, Renz JF. A critical evaluation of hepatic resection in cirrhosis: optimizing patient selection and outcomes. World J Surg 2005; 29:124-30. [PMID: 15654659 DOI: 10.1007/s00268-004-7633-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatic resection has long been the mainstay of treatment of primary liver cancers, particularly hepatocellular carcinoma (HCC). Because of the high incidence of cirrhosis in patients with HCC, the use of resection was initially limited by the ability of the cirrhotic liver to sustain the surgical insult and the mass reduction. Today, hepatectomy in cirrhosis is undergoing a remarkable evolution. Although surgical and anesthetic improvements have increased the safety of this option, the rapid development of alternative therapies has decreased the need for it. Local excision for small HCC is likely to be replaced by image-guided, percutaneous ablative techniques. Furthermore, total replacement of a cirrhotic liver may be a more effective long-term cure than resection. Unquestionably, resection remains the optimal approach for patients with large tumors and healthy underlying liver function. The role of rapidly evolving new approaches will remain the subject of intensive inquiry in the years to come. In this report, we have attempted to clarify current practice with respect to the evaluation, selection, and technique of resection in cirrhosis, and identify areas of active inquiry.
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Affiliation(s)
- Jean C Emond
- Center for Liver Disease and Transplantation, College of Physicians and Surgeons of Columbia University, 622 West 168th St., Room PH-14C, New York, NY, USA.
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Tepsiri N, Chaturat L, Sripa B, Namwat W, Wongkham S, Bhudhisawasdi V, Tassaneeyakul W. Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. World J Gastroenterol 2005; 11:2748-53. [PMID: 15884115 PMCID: PMC4305909 DOI: 10.3748/wjg.v11.i18.2748] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined.
METHODS: Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC50 values and the ratios of gene expression were analyzed by linear regression to predict their relationship.
RESULTS: Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC50 values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC50 values (<5 μmol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC50 values of etoposide, doxorubicin and pirarubicin (r = 0.86-0.98, P<0.05).
CONCLUSION: Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.
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Affiliation(s)
- Nisana Tepsiri
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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Brazeau DA. Combining genome-wide and targeted gene expression profiling in drug discovery: microarrays and real-time PCR. Drug Discov Today 2005; 9:838-45. [PMID: 15381136 DOI: 10.1016/s1359-6446(04)03231-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Daniel A Brazeau
- Pharmaceutical Genetics Laboratory, Department of Pharmaceutical Sciences, University at Buffalo State, University of New York, Buffalo, NY, USA.
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To KKW, Ho YP, Au-Yeung SCF. Synergistic interaction between platinum-based antitumor agents and demethylcantharidin. Cancer Lett 2004; 223:227-37. [PMID: 15896457 DOI: 10.1016/j.canlet.2004.10.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2004] [Revised: 10/26/2004] [Accepted: 10/28/2004] [Indexed: 11/26/2022]
Abstract
A novel series of TCM-platinum complexes [Pt(C8H8O5)(NH2R)2] 1-5, designed from incorporating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety was found to circumvent cisplatin resistance in mouse leukemia and human hepatocellular carcinoma. These properties are most likely due to the inclusion of the protein phosphatase 2A (PP2A)-inhibiting demethylcantharidin in the novel compounds. We have investigated the potential synergistic effect of combining demethylcantharidin with a platinum-based antitumor agent, such as cisplatin, carboplatin, or oxaliplatin in vitro against L1210 mouse leukemia and SK-Hep-1 human hepatocellular carcinoma, and in vivo against a SK-Hep-1 subcutaneous-inoculated xenograft in nude mice, using median effect analysis. Demethylcantharidin and the platinum antitumor agents were synergistic in all cell lines tested in vitro, and the most effective antiproliferative regimen was when demethylcantharidin was added 24 h before cisplatin. Synergistic antitumor activity was also demonstrated in vivo without undue toxicity; no excessive loss in mouse body weight or overt pathology were observed at the effective doses. The results support a new approach for augmenting cytotoxic effect of established Pt-based drugs with demethylcantharidin in treating human hepatocellular carcinoma and other solid tumors.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, China
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