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Stefanini B, Manfredi GF, D’Alessio A, Fulgenzi CA, Awosika N, Celsa C, Pirisi M, Rigamonti C, Burlone M, Vincenzi F, Minisini R, Gennari A, Yip V, Slater S, El-Shakankery K, Jain A, Tovoli F, Piscaglia F, Spalding D, Pai M, Pinato DJ. Delivering adjuvant and neoadjuvant treatments in the early stages of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:647-660. [PMID: 39435480 PMCID: PMC11601036 DOI: 10.1080/17474124.2024.2419519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. AREAS COVERED This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. EXPERT OPINION Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC.While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice.
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Affiliation(s)
- Bernardo Stefanini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia F. Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Claudia A.M. Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Nichola Awosika
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Mario Pirisi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Cristina Rigamonti
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Michela Burlone
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Vincent Yip
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Sarah Slater
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Karim El-Shakankery
- Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - Ananya Jain
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Duncan Spalding
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Madhava Pai
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 2018; 8:24604-24620. [PMID: 28445948 PMCID: PMC5421873 DOI: 10.18632/oncotarget.15599] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/06/2017] [Indexed: 12/17/2022] Open
Abstract
Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3′-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi’3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3′-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction. In conclusion, combination therapy of MEK and Pi3′-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.
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Funaki M, Kitabayashi J, Shimakami T, Nagata N, Sakai Y, Takegoshi K, Okada H, Murai K, Shirasaki T, Oyama T, Yamashita T, Ota T, Takuwa Y, Honda M, Kaneko S. Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. Sci Rep 2017; 7:16978. [PMID: 29208982 PMCID: PMC5717167 DOI: 10.1038/s41598-017-17285-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/22/2017] [Indexed: 02/07/2023] Open
Abstract
Sphingosine-1-phospate is a potent bioactive lipid metabolite that regulates cancer progression. Because sphingosine kinase 1 and sphingosine kinase 2 (SPHK 1/2) are both essential for sphingosine-1-phospate production, they could be a therapeutic target in various cancers. Peretinoin, an acyclic retinoid, inhibits post-therapeutic recurrence of hepatocellular carcinoma via unclear mechanisms. In this study, we assessed effects of peretinoin on SPHK expression and liver cancer development in vitro and in vivo. We examined effects of peretinoin on expression, enzymatic and promoter activity of SPHK1 in a human hepatoma cell line, Huh-7. We also investigated effects of SPHK1 on hepatocarcinogenesis induced by diethylnitrosamine using SPHK1 knockout mice. Peretinoin treatment of Huh-7 cells reduced mRNA levels, protein expression and enzymatic activity of SPHK1. Peretinoin reduced SPHK1 promoter activity; this effect of peretinoin was blocked by overexpression of Sp1, a transcription factor. Deletion of all Sp1 binding sites within the SPHK1 promoter region abolished SPHK1 promoter activity, suggesting that peretinoin reduced mRNA levels of SPHK1 via Sp1. Additionally, diethylnitrosamine-induced hepatoma was fewer and less frequent in SPHK1 knockout compared to wild-type mice. Our data showed crucial roles of SPHK1 in hepatocarcinogenesis and suggests that peretinoin prevents hepatocarcinogenesis by suppressing mRNA levels of SPHK1.
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Affiliation(s)
- Masaya Funaki
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Juria Kitabayashi
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan.
| | - Naoto Nagata
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuriko Sakai
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kai Takegoshi
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hikari Okada
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazuhisa Murai
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeru Oyama
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tsuguhito Ota
- Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoh Takuwa
- Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
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Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 2017. [PMID: 28445948 DOI: 10.18632/oncotarget.15599.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3'-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi'3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3'-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction.In conclusion, combination therapy of MEK and Pi3'-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.
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Dzik WH. Off-label Reports of New Biologics: Exciting New Therapy or Dubious Research? Examples From Recombinant Activated Factor VII. J Intensive Care Med 2016; 21:54-9. [PMID: 16705777 DOI: 10.1177/0885066605285223] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Walter H Dzik
- Blood Tranfusion Service, Massachusetts General Hospital, Boston, 02114, USA.
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Guan HB, Nie YZ, Zheng YW, Takiguchi K, Yu HW, Zhang RR, Li B, Tsuchida T, Taniguchi H. Acyclic retinoid induces differentiation and apoptosis of murine hepatic stem cells. Stem Cell Res Ther 2015; 6:51. [PMID: 25881300 PMCID: PMC4417297 DOI: 10.1186/s13287-015-0046-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 11/04/2014] [Accepted: 03/10/2015] [Indexed: 12/15/2022] Open
Abstract
Introduction The therapeutic potential of acyclic retinoid (ACR), a synthetic retinoid, has been confirmed in experimental and clinical studies. Therapeutic targets include precancerous and cancer stem cells. As ACR is also involved in developmental processes, its effect on normal hepatic stem cells (HpSCs) should be investigated for understanding the underlying mechanisms. Here, we examined effects of the acyclic retinoid peretinoin on fresh isolated murine HpSCs. Methods We isolated c-kit−CD29+CD49f+/lowCD45−Ter119− cells from murine fetal livers using flow cytometry. To evaluate the effect of ACR, we traced clonal expansion and analyzed cell differentiation as well as apoptosis during the induction process by immunofluorescent staining and marker gene expression. Results ACR dose-dependently inhibited HpSCs expansion. Stem cell clonal expansion was markedly inhibited during the culture period. Moreover, ACR showed a significant promotion of HpSC differentiation and induction of cellular apoptosis. The expression of stem cell marker genes, Afp, Cd44, and Dlk, was downregulated, while that of mature hepatocyte genes, Alb and Tat, and apoptosis-related genes, Annexin V and Caspase-3, were upregulated. Flow cytometry showed that the proportion of Annexin V-positive cells increased after ACR incubation compared with the control. Data obtained by immunofluorescent staining for albumin and Caspase-3 corroborated the data on gene expression. Finally, we found that ACR directly regulates the expression of retinoic acid receptors and retinoid X receptors. Conclusions These findings indicate that ACR inhibits the clonal expansion of normal HpSCs in vitro and promotes the differentiation of immature cells by regulating receptors of retinoic acid. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0046-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hong-Bin Guan
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
| | - Yun-Zhong Nie
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
| | - Yun-Wen Zheng
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan. .,Department of Advanced Gastroenterological Surgical Science and Technology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
| | - Kazuya Takiguchi
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
| | - Hong-Wei Yu
- Department of Histology and Embryology, Harbin Medical University, Harbin, 150081, China.
| | - Ran-Ran Zhang
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
| | - Bin Li
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, 97239, USA.
| | - Tomonori Tsuchida
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan. .,Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
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Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol 2015; 50:191-202. [PMID: 24728665 PMCID: PMC4318984 DOI: 10.1007/s00535-014-0956-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 03/19/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. METHODS Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). RESULTS Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. CONCLUSIONS Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.
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A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α. Diseases 2014. [DOI: 10.3390/diseases2030226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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Shimizu M, Shirakami Y, Hanai T, Imai K, Suetsugu A, Takai K, Shiraki M, Moriwaki H. Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids. Mol Nutr Food Res 2013; 58:124-35. [PMID: 24273224 DOI: 10.1002/mnfr.201300538] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 09/10/2013] [Accepted: 09/16/2013] [Indexed: 12/11/2022]
Abstract
The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy.
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Affiliation(s)
- Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
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Honda M, Yamashita T, Yamashita T, Arai K, Sakai Y, Sakai A, Nakamura M, Mizukoshi E, Kaneko S. Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma. BMC Cancer 2013; 13:191. [PMID: 23587162 PMCID: PMC3660229 DOI: 10.1186/1471-2407-13-191] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 03/08/2013] [Indexed: 12/20/2022] Open
Abstract
Background The acyclic retinoid, peretinoin, has been shown to be effective for suppressing hepatocellular carcinoma (HCC) recurrence after definitive treatment in a small-scale randomized clinical trial. However, little has been documented about the mechanism by which peretinoin exerts its inhibitory effects against recurrent HCC in humans in vivo. Methods Twelve hepatitis C virus-positive patients whose HCC had been eradicated through curative resection or ablation underwent liver biopsy at baseline and week 8 of treatment with either a daily dose of 300 or 600 mg peretinoin. RNA isolated from biopsy samples was subjected to gene expression profile analysis. Results Peretinoin treatment elevated the expression levels of IGFBP6, RBP1, PRB4, CEBPA, G0S2, TGM2, GPRC5A, CYP26B1, and many other retinoid target genes. Elevated expression was also observed for interferon-, Wnt-, and tumor suppressor-related genes. By contrast, decreased expression levels were found for mTOR- and tumor progression-related genes. Interestingly, gene expression profiles for week 8 of peretinoin treatment could be classified into two groups of recurrence and non-recurrence with a prediction accuracy rate of 79.6% (P<0.05). In the liver of patients with non-recurrence, expression of PDGFC and other angiogenesis genes, cancer stem cell marker genes, and genes related to tumor progression was down-regulated, while expression of genes related to hepatocyte differentiation, tumor suppression genes, and other genes related to apoptosis induction was up-regulated. Conclusions Gene expression profiling at week 8 of peretinoin treatment could successfully predict HCC recurrence within 2 years. This study is the first to show the effect of peretinoin in suppressing HCC recurrence in vivo based on gene expression profiles and provides a molecular basis for understanding the efficacy of peretinoin.
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Affiliation(s)
- Masao Honda
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, 13-1Takara-machi, Kanazawa 920-0934, Japan.
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Shimizu M, Shirakami Y, Imai K, Takai K, Moriwaki H. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis. J Carcinog 2012; 11:11. [PMID: 23230390 PMCID: PMC3515920 DOI: 10.4103/1477-3163.100398] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 07/15/2012] [Indexed: 12/28/2022] Open
Abstract
One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of “clonal deletion and inhibition” therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss “combination chemoprevention” using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.
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Affiliation(s)
- Masahito Shimizu
- Department of Medicine, Gifu University Graduate School of Medicine 1-1 Yanagido, Gifu 501-1194, Japan
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Okada H, Honda M, Campbell JS, Sakai Y, Yamashita T, Takebuchi Y, Hada K, Shirasaki T, Takabatake R, Nakamura M, Sunagozaka H, Tanaka T, Fausto N, Kaneko S. Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. Cancer Res 2012; 72:4459-71. [PMID: 22651928 DOI: 10.1158/0008-5472.can-12-0028] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) often develops in association with liver cirrhosis, and its high recurrence rate leads to poor patient prognosis. Although recent evidence suggests that peretinoin, a member of the acyclic retinoid family, may be an effective chemopreventive drug for HCC, published data about its effects on hepatic mesenchymal cells, such as stellate cells and endothelial cells, remain limited. Using a mouse model in which platelet-derived growth factor (PDGF)-C is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis, steatosis, and eventually, HCC development, we show that peretinoin significantly represses the development of hepatic fibrosis and tumors. Peretinoin inhibited the signaling pathways of fibrogenesis, angiogenesis, and Wnt/β-catenin in Pdgf-c transgenic mice. In vitro, peretinoin repressed the expression of PDGF receptors α/β in primary mouse hepatic stellate cells (HSC), hepatoma cells, fibroblasts, and endothelial cells. Peretinoin also inhibited PDGF-C-activated transformation of HSCs into myofibroblasts. Together, our findings show that PDGF signaling is a target of peretinoin in preventing the development of hepatic fibrosis and HCC.
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Affiliation(s)
- Hikari Okada
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8641, Japan
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Kitagawa J, Hara T, Tsurumi H, Ninomiya S, Ogawa K, Adachi S, Kanemura N, Kasahara S, Shimizu M, Moriwaki H. Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2. J Cancer Res Clin Oncol 2011; 137:779-87. [PMID: 20676681 DOI: 10.1007/s00432-010-0938-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 07/13/2010] [Indexed: 10/19/2022]
Abstract
PURPOSE The aim of this study was to assess the effects of acyclic retinoid (ACR) and vitamin K(2) (VK(2)) in HL-60 cells. METHODS We used HL-60 cells, and the Trypan Blue dye exclusion method was used for cell proliferation assays. For detection of apoptosis, the Annexin V-binding capacity of treated cells was examined by flow cytometry. To evaluate the cell cycle, we used a FITC BrdU Flow KIT and flow cytometry. Total extracted and equivalent amounts of protein were examined by Western blotting using specific antibodies. RESULTS ACR and VK(2) dose dependently inhibited the proliferation of HL-60 cells. These two agents in combination synergistically inhibited cell growth and induced apoptosis. VK(2) inhibited activation of the Ras/MAPK signaling pathway, and ACR plus VK(2) cooperatively inhibited phosphorylation of RXRα and the growth of HL-60 cells. Moreover, ACR and VK(2) induced increases in G0/G1 phase HL-60 cells, alone and synergistically in combination. CONCLUSION The synergistic effects of ACR and VK(2) on HL-60 cells may provide a novel strategy for treating leukemia.
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Affiliation(s)
- Junichi Kitagawa
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
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Sherman H, Gutman R, Chapnik N, Meylan J, le Coutre J, Froy O. All-trans retinoic acid modifies the expression of clock and disease marker genes. J Nutr Biochem 2011; 23:209-17. [PMID: 21497500 DOI: 10.1016/j.jnutbio.2010.11.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Revised: 10/19/2010] [Accepted: 11/18/2010] [Indexed: 12/22/2022]
Abstract
Restricted feeding (RF), a regimen that restricts the duration of food availability with no calorie restriction, entrains the circadian clock in peripheral tissues. Restricted feeding leads to high-amplitude circadian rhythms, which have been shown to promote wellness and reduce disease and inflammatory markers. Retinoids, such as all-trans retinoic acid (ATRA), act as anti-inflammatory agents. Thus far, the effect of ATRA combined with RF on the ability to delay the occurrence of age-associated changes, such as cancer and inflammation, is not known. We measured circadian expression of clock genes, disease marker genes and inflammatory markers in the serum, liver and jejunum in mice fed ad libitum (AL) or RF supplemented with 15 or 250 μg/kg body/day ATRA for 16 weeks. Our results show that ATRA supplementation led to phase shifts and reduced amplitudes in clock genes. Under AL, ATRA reduced the average daily messenger RNA (mRNA) levels of some disease markers, such as liver Afp and jejunum Afp, Alt and Gadd45β and aspartate transaminase (AST) protein in the serum, but increased the expression level of liver Crp mRNA. Under RF, ATRA reduced the average daily levels of jejunum Alt and Gadd45β and AST protein in the serum, but increased liver Afp, Alt, Gadd45β and Arginase mRNA. Altogether, our findings suggest that ATRA strongly affects circadian oscillation and disease marker levels. Moreover, its impact is different depending on the feeding regimen (AL or RF).
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Affiliation(s)
- Hadas Sherman
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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A proteomic approach to characterizing ciglitazone-induced cancer cell differentiation in Hep-G2 cell line. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2009; 1794:615-26. [DOI: 10.1016/j.bbapap.2009.01.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2008] [Revised: 12/15/2008] [Accepted: 01/09/2009] [Indexed: 01/22/2023]
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Shimizu M, Takai K, Moriwaki H. Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. Cancer Sci 2009; 100:369-74. [PMID: 19068086 PMCID: PMC11159360 DOI: 10.1111/j.1349-7006.2008.01045.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is 'clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXRalpha due to phosphorylation by the Ras-mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXRalpha proteins. In conclusion, the inhibition of RXRalpha phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXRalpha, may thus play a critical role in preventing the development of multicentric HCC.
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Affiliation(s)
- Masahito Shimizu
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
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17
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Yin YQ, Wang XH, Ma P, Fu LY, Jiang T, Wang Y. Interon-gamma enhances the antitumor effect of all-trans retinoic acid on hepatocellular carcinoma cells by inhibiting the expression of nuclear factor-kappaB. Chin J Cancer Res 2008. [DOI: 10.1007/s11670-008-0211-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Higginbotham KB, Lozano R, Brown T, Patt YZ, Arima T, Abbruzzese JL, Thomas MB. A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma. J Cancer Res Clin Oncol 2008; 134:1325-35. [PMID: 18504614 DOI: 10.1007/s00432-008-0406-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Accepted: 04/23/2008] [Indexed: 02/06/2023]
Abstract
PURPOSE Preclinical models showed TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has anti-tumor activity in hepatocellular carcinoma (HCC). A phase I/II study was performed in advanced HCC patients (pts). PATIENTS AND METHODS Thirty-three patients were enrolled. During Phase I, pts received 40 mg daily for 14 days q3 weeks; 2 of 5 patients developed DLT so dose was reduced to 20 mg/day. Twenty-eight patients received 20 mg/day. RESULTS No pt had a CR or PR, but 12 of 21 (57%) had SD. Two pts (9.5%) had late PR after discontinuing TAC-101. Median survival (MS) for all 28 pts treated with 20 mg/day was 12.7 months (95% CI 8.8-22.7); MS for 21 evaluable pts was 19.2 months (95% CI 10.4-27.6). CONCLUSIONS 20 mg of TAC- was well tolerated. Significant disease stabilization (12/21 pts, 57%), 2 late PRs, and prolonged MS (19.2 months) suggest that TAC-101 provides meaningful patient benefit.
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Affiliation(s)
- Kimberly B Higginbotham
- Department of Gastrointestinal Medical Oncology Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
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Moriwaki H, Shimizu M, Okuno M, Nishiwaki-Matsushima R. Chemoprevention of liver carcinogenesis with retinoids: Basic and clinical aspects. Hepatol Res 2007; 37 Suppl 2:S299-302. [PMID: 17877499 DOI: 10.1111/j.1872-034x.2007.00201.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The strategy to prevent liver carcinogenesis consists of: (i) antiviral modalities such as vaccination, lamivudin, and interferon; (ii) anti-inflammatory modality; and (iii) chemoprevention using such compounds as retinoid analog and vitamin K. Cancer chemoprevention is defined as an approach where natural or synthetic chemical compound works to arrest or reverse premalignant cells by using physiological pathways. As a consequence, such a clone of premalignant cells is eradicated (clonal deletion) by differentiation induction or apoptosis, and thus the process toward the development of clinically detectable cancer is disrupted. A particularly effective candidate target of chemoprevention in liver diseases is an advanced stage of chronic hepatitis, that is supposed to contain transformed hepatocyte clone(s); that is, primary prevention from liver cirrhosis and prevention of recurrent and second primary hepatocellular carcinoma following the treatment of the initial cancer. Retinoid is a collective term of vitamin A analog that binds to nuclear retinoid receptors;retinoic acid receptors (RAR) and retinoid X receptors (RXR). After ligand coupling, these receptors form homo- or heterodimers, bind to the response element (RARE or RXRE) upstream of the target gene, and regulate the gene expression as a transcriptional factor. Biological phenotypes of such transcriptional regulation by retinoid include cellular differentiation, tissue morphogenesis, and programmed cell death (apoptosis). Due to these functions, retinoid analogs are clinically tried to prevent/treat carcinoma in a wide variety of organs including head and neck cancer, uterine cervical cancer, certain leukemia and liver cancer. In this article, clinical trials of retinoid analog to inhibit second primary hepatoma, supposed molecular mechanism of the action of the compound, and aberrant metabolism of RXR and its role in liver carcinogenesis are briefly reviewed.
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Affiliation(s)
- Hisataka Moriwaki
- Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan
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20
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Ho JCY, Cheung ST, Poon WS, Lee YT, Ng IOL, Fan ST. Down-regulation of retinol binding protein 5 is associated with aggressive tumor features in hepatocellular carcinoma. J Cancer Res Clin Oncol 2007; 133:929-36. [PMID: 17497168 DOI: 10.1007/s00432-007-0230-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2006] [Accepted: 03/23/2007] [Indexed: 11/26/2022]
Abstract
PURPOSE Acyclic retinoid (ACR) has been shown to be a promising chemopreventive agent for hepatocellular carcinoma (HCC) after curative resection. The effects of retinoid are mediated by retinol-binding proteins (RBPs) through regulating cell proliferation and differentiation. PATIENTS AND METHODS This study investigated the clinical significance of RBP5 in HCC. RBP5 mRNA level was examined by real-time quantitative PCR on 52 matched tumor and adjacent non-tumor liver tissues, and on ten normal livers. Expression of RBP5 protein was examined using Western blotting analysis and immunohistochemistry. RESULTS Down-regulation of RBP5 was found in HCC tissues at both mRNA and protein levels. Decreased RBP5 level was closely related to poor differentiation (P=0.02) and large tumor size (P=0.01). Low level of RPB5 was associated with poor overall survival (P=0.02), and was an independent prognostic factor for HCC. CONCLUSIONS Our study revealed that RBP5 down-regulation in HCC was associated with aggressive tumor features, suggesting an important role of RPB5 in HCC progression.
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Affiliation(s)
- Jenny C Y Ho
- Department of Surgery, The University of Hong Kong, L9-55, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road Pokfulam, Hong Kong, China
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Yano H, Basaki Y, Oie S, Ogasawara S, Momosaki S, Akiba J, Nishida N, Kojiro S, Ishizaki H, Moriya F, Kuratomi K, Fukahori S, Kuwano M, Kojiro M. Effects of IFN-alpha on alpha-fetoprotein expressions in hepatocellular carcinoma cells. J Interferon Cytokine Res 2007; 27:231-8. [PMID: 17348822 DOI: 10.1089/jir.2006.0135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We investigated the effects of pegylated (PEG)-IFN-alpha2b on alpha-fetoprotein (AFP) expression as demonstrated by protein and mRNA levels in six human hepatocellular carcinoma (HCC) cell lines. The number of KIM-1 cells in culture with PEG-IFN-alpha2b decreased between 24 amd 240 h, whereas the levels of intracellular and secreted AFP per cellular protein increased (except at 192 h), with levels 1.9-fold and 2.9-fold higher at maximum, respectively, than cells without PEG-IFN-alpha2b (control). The mRNA level increased between 72 and 192 h, when the level was 3-fold higher than that of the control. In the 72-h culture with 40-5000 IU/mL PEG-IFN-alpha2b, there were dose-dependent increases in AFP protein and mRNA expression and dose-dependent decrease in cell number resulting from apoptosis and blockage of the cell cycle at the S-phase. The rate of fucosylated AFP in the cell lysate decreased in a dose-dependent and time-dependent manner. In the PEG-IFN-alpha2b culture of the other five HCC cell lines, cell proliferation was suppressed, but the expressions of AFP protein and mRNA increased in only two cell lines, and suppression of cell proliferation was not related to the increase in AFP expressions. Our findings demonstrated that PEG-IFN-alpha2b induces an increase in AFP expression at both the protein and mRNA levels.
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Affiliation(s)
- Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
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Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, Moriwaki H. Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells. Cancer Sci 2007; 98:431-7. [PMID: 17270033 PMCID: PMC11158363 DOI: 10.1111/j.1349-7006.2006.00384.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, effective chemopreventive and chemotherapeutic agents for this cancer have not yet been developed. In clinical trials acyclic retinoid (ACR) and vitamin K(2) (VK(2)) decreased the recurrence rate of HCC. In the present study we examined the possible combined effects of ACR or another retinoid 9-cis retinoic acid (9cRA) plus VK(2) in the HuH7 human HCC cell line. We found that the combination of 1.0 microM ACR or 1.0 microM 9cRA plus 10 microM VK(2) synergistically inhibited the growth of HuH7 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VK(2) also acted synergistically to induce apoptosis in HuH7 cells. Treatment with VK(2) alone inhibited phosphorylation of the retinoid X receptor (RXR)alpha protein, which is regarded as a critical factor for liver carcinogenesis, through inhibition of Ras activation and extracellular signal-regulated kinase phosphorylation. Moreover, the inhibition of RXRalpha phosphorylation by VK(2) was enhanced when the cells were cotreated with ACR. The combination of retinoids plus VK(2) markedly increased both the retinoic acid receptor responsive element and retinoid X receptor responsive element promoter activities in HuH7 cells. Our results suggest that retinoids (especially ACR) and VK(2) cooperatively inhibit activation of the Ras/MAPK signaling pathway, subsequently inhibiting the phosphorylation of RXRalpha and the growth of HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
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Affiliation(s)
- Toh Kanamori
- Department of Medicine, Gifu University School of Medicine, Gifu, Japan
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Abstract
The development of hepatocellular carcinoma (HCC), the mechanisms of hepatocarcinogenesis, the prevention of HCC, and screening for HCC will be discussed. Cirrhosis has been considered as a pre-neoplastic condition for the development of HCC. The worldwide incidence of HCC differs according to different hepatitis viruses, and information is lacking. Hepatocarcinogenesis is a multistep process involving a number of different genetic alterations and is poorly understood. Interferon should help prevent the development of HCC in patients with chronic hepatitis C. Screening is the only practical approach for improving the management of HCC patients, as early detection increases the application of curative treatments. However, the cost-effectiveness of various screening strategies needs to be analysed.
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Affiliation(s)
- Hiroaki Okuda
- Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
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Sano T, Kagawa M, Okuno M, Ishibashi N, Hashimoto M, Yamamoto M, Suzuki R, Kohno H, Matsushima-Nishiwaki R, Takano Y, Tsurumi H, Kojima S, Friedman SL, Moriwaki H, Tanaka T. Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-alpha-expressing oval-like cells and activated hepatic stellate cells. Nutr Cancer 2005; 51:197-206. [PMID: 15860442 DOI: 10.1207/s15327914nc5102_10] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
We investigated the preventive effects of a synthetic acyclic retinoid, NIK-333, on the early and late events of hepatocarcinogenesis in male F344 rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). NIK-333 was administered once a day on consecutive days at a dose of 10, 40, or 80 mg/kg body weight along with the supplementation with 3'-MeDAB-containing diet for 16 wk. Animals from each group were sacrificed at 4 and 16 wk after the commencement of the experiment to determine the effect of NIK-333 on the early and late stages of carcinogenesis, respectively. NIK-333 suppressed the emergence of both oval-like cells expressing transforming growth factor (TGF)-alpha, putative progenitors of hepatocellular carcinoma (HCC), and activated hepatic stellate cells, major matrix-producing cells of the liver, in the early stage and inhibited the incidence of HCC in the late phase. These results suggest that NIK-333 is a promising drug for the chemoprevention of HCC by uniquely suppressing the early events of hepatocarcinogenesis, that is, development of both oval-like cells and fibrogenesis.
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Affiliation(s)
- Tetsuro Sano
- Pharmaceutical Research Laboratories, Nikken Chemicals Co., Saitama, Japan
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Takai K, Okuno M, Yasuda I, Matsushima-Nishiwaki R, Uematsu T, Tsurumi H, Shiratori Y, Muto Y, Moriwaki H. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 2005; 48:39-45. [PMID: 15785088 DOI: 10.1159/000082093] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Oral administration with acyclic retinoid, a synthetic vitamin A analog, for a limited period of 12 months (48 weeks) prevented the development of second primary hepatocellular carcinoma (HCC) and also improved the survival of patients who underwent curative treatments of the initial tumor. Following that randomized controlled study reported in 1996 and 1999, we have continued to follow up the patients by medical imaging and blood chemical analyses, and found that the preventive effect of acyclic retinoid lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). The retinoid's effect was not mediated by reduction in hepatic necro-inflammation since no significant decrease in serum aminotransferase activity was seen in the retinoid group. Such observation seems quite distinct from the cancer-preventive mechanism of interferon, a potent immunopreventive agent for HCC. We have also shown here the reduction by the retinoid in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), both of which indicate the presence of latent HCC cells. These results suggest that acyclic retinoid may delete such malignant clones before they expand to clinically detectable tumors and thereby inhibited second primary HCC. Once such latent clones are eradicated, it may well take at least several years for the next cancer clone to arise clinically. This may possibly explain a reason for the long-term effect of the retinoid even after the limited period of administration.
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Affiliation(s)
- Koji Takai
- Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan
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Kagechika H, Shudo K. Synthetic Retinoids: Recent Developments Concerning Structure and Clinical Utility. J Med Chem 2005; 48:5875-83. [PMID: 16161990 DOI: 10.1021/jm0581821] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Hiroyuki Kagechika
- School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
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Lam MSH, Sims-McCallum RP. Recombinant Factor VIIa in the Treatment of Non-Hemophiliac Bleeding. Ann Pharmacother 2005; 39:885-91. [PMID: 15784806 DOI: 10.1345/aph.1e553] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE: To review the clinical evidence for the use of recombinant factor VIIa (rFVIIa) in the prevention and/or treatment of bleeding in non-hemophiliac patients. DATA SOURCES: A MEDLINE search (1966–December 2004) was conducted to identify pertinent literature. Results were limited to English-language reports and clinical trials. References of relevant articles and selected abstracts presented at scientific meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Human data from prospective and retrospective studies that examined the hemostatic effect of rFVIIa in non-hemophiliac patients were reviewed, with a focus on surgical prophylaxis, liver disease, intractable bleeding associated with trauma and surgery, and anticoagulation reversal. DATA SYNTHESIS: Results from limited controlled trials on the use of rFVIIa as an adjunct for prevention of bleeding in surgery and liver diseases have not been consistent. For treatment of intractable bleeding, earlier use of rFVIIa in one trauma trial was shown to decrease the number of blood transfusions, but no differences in terms of clinical outcomes were observed in all trials. Controlled trials do not suggest an increased risk of thrombotic events. Optimal dosing and timing of administration have yet to be defined. CONCLUSIONS: Until further prospective controlled data are available, it is recommended that conventional intervention for prevention and control of hemorrhage in non-hemophiliac patients should remain the standard of care. Close monitoring of coagulation parameters is recommended before, during, and after therapy, especially in high-risk patients. Pharmacoeconomic analysis may be useful to help control costs and maximize clinical benefits.
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Affiliation(s)
- Masha S H Lam
- Hematology/Oncology, Shands, University of Florida, Gainesville, FL, USA.
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Harimoto N, Taketomi A, Kitagawa D, Kuroda Y, Itoh S, Gion T, Tanaka S, Shirabe K, Shimada M, Maehara Y. The newly established human hepatocyte cell line: application for the bioartificial liver. J Hepatol 2005; 42:557-64. [PMID: 15763342 DOI: 10.1016/j.jhep.2004.11.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2004] [Revised: 11/05/2004] [Accepted: 11/25/2004] [Indexed: 01/29/2023]
Abstract
BACKGROUND/AIMS Human hepatocyte cell lines are reported to lose many of their biochemical functions in a hybrid artificial liver support system (HALSS). Differentiation therapy is useful to up-regulate liver function. METHODS The human hepatoblastoma cell line HepG2 was transfected with HSV/tk gene. Albumin synthesis and ammonia removal activity were evaluated when HepG2/tk was cultured with histone deacetylase inhibitor (FR228) and peroxisome proliferator activated receptor-gamma ligand (pioglitazone). To investigate the function of HepG2/tk in vivo, cell transplantation for 90% hepatectonized rats was conducted. RESULTS We established stable cell lines which expressed HSV/tk and were sensitive to gancyclovir in vitro and in vivo. Both albumin synthesis rate and ammonia removal rate improved for HepG2/tk incubated with FR228 and pioglitazone for 3 days, which induced nuclear transport of p21. Rats with intrasplenic injection of HepG2/tk precultured for 3 days with FR228 and pioglitazone survived significantly longer than the control rats. The ammonia and total bilirubin concentrations were significantly lower in the test group than in the control group. The injection of gancyclovir inhibited the prolonged survival of the rats with precultured HepG2/tk. CONCLUSIONS HepG2/tk is safe as well as enhancing high levels of liver function. It will be a potential cell source for HALLS in the future.
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Affiliation(s)
- Norifumi Harimoto
- The Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Shimizu M, Suzui M, Deguchi A, Lim JTE, Xiao D, Hayes JH, Papadopoulos KP, Weinstein IB. Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells. Clin Cancer Res 2005; 10:6710-21. [PMID: 15475462 DOI: 10.1158/1078-0432.ccr-04-0659] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Blotting, Western
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Adhesion Molecules/metabolism
- Cell Cycle Proteins/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Chloramphenicol O-Acetyltransferase/genetics
- Chloramphenicol O-Acetyltransferase/metabolism
- Cyclic GMP/metabolism
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Cyclin-Dependent Kinase Inhibitor p21
- Cytoskeletal Proteins/metabolism
- Dose-Response Relationship, Drug
- Drug Synergism
- G1 Phase/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Intracellular Space/drug effects
- Intracellular Space/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Microfilament Proteins
- Models, Biological
- Phosphoproteins/metabolism
- Phosphorylation/drug effects
- Promoter Regions, Genetic/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Retinoic Acid/genetics
- Receptors, Retinoic Acid/metabolism
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Response Elements/genetics
- Resting Phase, Cell Cycle/drug effects
- Retinoblastoma Protein/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sulindac/analogs & derivatives
- Sulindac/pharmacology
- Trans-Activators/metabolism
- Transfection
- Tretinoin/analogs & derivatives
- Tretinoin/pharmacology
- Tumor Suppressor Protein p53/metabolism
- beta Catenin
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Affiliation(s)
- Masahito Shimizu
- Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
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30
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Jiang SY, Chou JM, Leu FJ, Hsu YY, Shih YL, Yu JC, Lee MS, Shyu RY. Decreased expression of type II tumor suppressor gene RARRES3 in tissues of hepatocellular carcinoma and cholangiocarcinoma. World J Gastroenterol 2005; 11:948-53. [PMID: 15742394 PMCID: PMC4250783 DOI: 10.3748/wjg.v11.i7.948] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [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 analyze the expression of retinoic acid receptor responder 3 (RARRES3) protein in paraffin-embedded tissues of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), and the correlation of RARRES3 production with tumor differentiation.
METHODS: Expression of RARRES3 in tissues from 21 CC (10 well-, 7 moderately- and 4 poorly-differentiated) and 32 HCC was determined by immunohistochemistry.
RESULTS: Among 21 CC tissues, RARRES3 was detected in 8 (80%) of 10 well-differentiated tumors. Only 2 (18.2%) out of 11 tumors with moderate or poor differentiation showed positive RARRES3 expression. RARRES3 expression in well-differentiated CC was significantly higher than that in tumors with moderate or poor differentiation (Fisher exact test, P<0.01). Expression of RARRES3 was not different between early (I and II) and late (III and IV) stages of CC. Among 30 HCC tissues, 17 (56.7%) weakly expressed RARRES3 in HCC cells, and 25 (83.3%) normal tissues adjacent to HCC expressed the protein. RARRES3 expression was significantly decreased in HCC tissues compared to that in adjacent normal tissues (logistic regression analysis, OR = 0.27, 95% CI (0.11-0.62), P<0.01).
CONCLUSION: Expression of RARRES3 is positively correlated to well-differentiated CC, which supports the role of RARRES3 in malignant epithelial differentiation of the tumor. The decrease in RARRES3 expression in tissues of HCC and CC with moderate and poor differentiation suggests that altered RARRES3 expression may play a role in the carcinogenesis of the liver and biliary tract.
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Affiliation(s)
- Shun-Yuan Jiang
- Section of Gastroenterology, Tri-Service General Hospital, 325 Chengung Rd, Sec. 2, Taipei 114, Taiwan, China
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31
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Wang L, Levin MS. Suppression of FGF signaling: a putative mechanism for the chemopreventive effects of acyclic retinoid in hepatocellular carcinoma. Gastroenterology 2005; 128:228-31. [PMID: 15633140 DOI: 10.1053/j.gastro.2004.11.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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32
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De Gasperi A, Baudo F, De Carlis L. Recombinant FVII in orthotopic liver transplantation (OLT): a preliminary single centre experience. Intensive Care Med 2004; 31:315-6. [PMID: 15592812 DOI: 10.1007/s00134-004-2525-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2004] [Accepted: 11/10/2004] [Indexed: 10/26/2022]
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33
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Abstract
UNLABELLED THE PURPOSE OF THIS REVIEW: The purpose of this review is to summarize the safety and efficacy of recombinant activated factor VII in diverse clinical settings based on recent published anecdotal experiences and early results from prospective trials. RECENT FINDINGS Recombinant activated factor VII is increasingly being used for off-label treatment and prophylaxis of bleeding in non-hemophiliac patients. Case reports would suggest that recombinant activated factor VII is an efficacious and safe "universal hemostatic agent". To date, results of several randomized control trials investigating recombinant activated factor VII in non-hemophiliacs have been published as abstracts, supporting recombinant activated factor VII safety, but not its efficacy. SUMMARY Until the results of additional prospective trials are available, clinicians, who manage patients with challenging hemostatic complications, and transfusion medicine specialists should collaborate to develop local policies for off-label utilization of recombinant activated factor VII.
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Affiliation(s)
- Erik J Uhlmann
- Division of Laboratory Medicine, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
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34
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Shimizu M, Suzui M, Deguchi A, Lim JTE, Weinstein IB. Effects of Acyclic Retinoid on Growth, Cell Cycle Control, Epidermal Growth Factor Receptor Signaling, and Gene Expression in Human Squamous Cell Carcinoma Cells. Clin Cancer Res 2004; 10:1130-40. [PMID: 14871993 DOI: 10.1158/1078-0432.ccr-0714-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
We described recently the growth inhibitory effects of the novel compound acyclic retinoid (ACR) in human hepatoma cell lines (M. Suzui et al., Cancer Res., 62: 3997-4006, 2002). In this study we examined the cellular and molecular effects of ACR on human squamous cell carcinoma (SCC) cells. ACR inhibited growth of the esophageal SCC cell line HCE7, and the head and neck SCC cell lines YCU-N861 and YCU-H891, with IC(50) values of approximately 10, 25, and 40 microM, respectively. Detailed studies were then done with HCE7 cells. Treatment of these cells with 10 microM ACR caused an increase of cells in G(0)-G(1) and induced apoptosis. This was associated with two phases of molecular events. During phase 1, which occurred within 6-12 h, there was an increase in the retinoic acid receptor beta (RARbeta) and p21(CIP1) proteins, and their corresponding mRNAs, and a decrease in the hyperphosphorylated form of the retinoblastoma protein. During phase 2, which occurred at approximately 24 h, there was a decrease in the cellular level of transforming growth factor alpha, and the phosphorylated (i.e., activated) forms of the epidermal growth factor receptor, Stat3, and extracellular signal-regulated kinase proteins, and a decrease in both cyclin D1 protein and mRNA. Reporter assays indicated that ACR inhibited the transcriptional activity of the cyclin D1, c-fos, and activator protein promoters. On the other hand, ACR markedly stimulated the activity of a retinoic acid response element-CAT reporter when the cells were cotransfected with a RARbeta expression vector. A hypothetical model explaining these two phases is presented. The diverse effects that we obtained with ACR suggest that this agent might be useful in the chemoprevention and/or therapy of human SCCs.
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Affiliation(s)
- Masahito Shimizu
- Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 701 West 168th Street, New York, NY 10032-2704, USA
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35
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Matsushima-Nishiwaki R, Okuno M, Takano Y, Kojima S, Friedman SL, Moriwaki H. Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis 2003; 24:1353-9. [PMID: 12807734 DOI: 10.1093/carcin/bgg090] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.
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36
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Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, Yasuda I, Yamada Y, Akita K, Sano T, Shimada J, Kojima S, Okano Y, Friedman SL, Moriwaki H. Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. Hepatology 2002; 36:1115-24. [PMID: 12395321 DOI: 10.1053/jhep.2002.36369] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-alpha) and IFN-beta induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7, HuH7, PLC/PRF/5, HLE, and HLF). This synergism was only observed when cells were pretreated with the acyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with antitype 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2', 5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably because of a lack of IFNR and STAT1 up-regulation. In conclusion, these results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-beta.
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Affiliation(s)
- Akihiro Obora
- First Department of Internal Medicine and Department of Pathobiochemistry, Gifu University School of Medicine, Japan
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