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Vorontsova JE, Cherezov RO, Kuzin BA, Simonova OB. Aryl-Hydrocarbon Receptor as a Potential Target for Anticancer Therapy. BIOCHEMISTRY (MOSCOW), SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY 2019. [DOI: 10.1134/s1990750819010116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Vorontsova JE, Cherezov RO, Kuzin BA, Simonova OB. [Aryl-hydrocarbon receptor as a potential target for anticancer therapy]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2018; 64:397-415. [PMID: 30378556 DOI: 10.18097/pbmc20186405397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aryl-hydrocarbon receptor (Aryl Hydrocarbon Receptor, AHR) is a ligand-dependent transcription factor, whose functions are related to xenobiotic detoxification, response to inflammation, and maintenance of tissue homeostasis. Recent investigations suggest that AHR also plays an important role in the processes of carcinogenesis. Increased expression of AHR is observed in several types of tumors and tumor cell lines. In addition, it turned out that the composition of pharmaceutical drugs used in oncotherapy includes some ligands AHR. These facts allow us to consider an aryl-hydrocarbon receptor as a potential target for anticancer therapy, especially for the treatment of severe cancers whose treatment options are very limited or do not exist at all. In this review the examples of AHR ligands' effect on tumor cell cultures and on model mice lines with AHR-dependent response are discussed.
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Affiliation(s)
- J E Vorontsova
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
| | - R O Cherezov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
| | - B A Kuzin
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
| | - O B Simonova
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
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Ikuta S, Aihara T, Yamanaka N. Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma: a retrospective single-institution study. Contemp Oncol (Pozn) 2018; 22:165-171. [PMID: 30455588 PMCID: PMC6238090 DOI: 10.5114/wo.2018.78948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 07/15/2018] [Indexed: 01/05/2023] Open
Abstract
AIM OF THE STUDY To evaluate the efficacy of sequential combination therapy using sorafenib and hepatic arterial infusion chemotherapy (HAIC) in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma (HCC). MATERIAL AND METHODS We recruited 98 BCLC stage B/C HCC patients at our institute, who received either sorafenib monotherapy or planned sequential sorafenib-HAIC combination therapy. A total of 26 patients (combination group) received sorafenib for one or two months, followed by HAIC with a single dose of cisplatin-lipiodol suspension and a continuous infusion of 5-fluorouracil. Sorafenib-HAIC cycles were repeated every 2-3 months. The remaining 72 patients (control group) were treated with sorafenib alone. Clinical characteristics and treatment outcomes were compared between the groups. Inverse probability weighting (IPW) using propensity scores was applied to adjust for the between-group differences in baseline characteristics. RESULTS The combination group had a significantly lower frequency of extrahepatic metastasis and BCLC stage C disease compared with the control group but had more intrahepatic lesions. The crude median overall survival (OS) was 17.1 months in the combination group compared with 9.7 months in the control group (p = 0.01). The objective response rate was 23.1% in the combination group vs. 6.9% in the control group (p = 0.06). Multivariate analysis identified receipt of sorafenib-HAIC combination (HR: 0.521, 95% CI: 0.297-0.915, p = 0.02) and α-fetoprotein (≥ 400 ng/ml) at baseline as independent factors associated with OS. After adjustment with IPW the combination group still had significantly better OS than the control group (p = 0.04). CONCLUSIONS The sequential sorafenib-HAIC combination can be an effective and promising treatment option for selected patients with BCLC stage B/C HCC.
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Affiliation(s)
- Shinichi Ikuta
- Department of Surgery, Meiwa Hospital, Nishinomiya, Japan
| | - Tsukasa Aihara
- Department of Surgery, Meiwa Hospital, Nishinomiya, Japan
| | - Naoki Yamanaka
- Department of Surgery, Meiwa Hospital, Nishinomiya, Japan
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Sun H, Ni J, Jiang X, Chen D, Chen Y, Xu L. The effect of lipiodol deposition in HCC after TACE on the necrosis range of PMCT. Onco Targets Ther 2017; 10:3835-3842. [PMID: 28814882 PMCID: PMC5546818 DOI: 10.2147/ott.s137312] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Objective To study the impact of lipiodol deposition in the lesion of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) on the necrosis area of percutaneous microwave coagulation therapy (PMCT). Materials and methods A total of 44 patients with HCC with 56 nodules, with a size ranging from 1.5 to 3.5 cm, was selected in our study. About 23 patients (26 nodules) underwent PMCT treatment only as Group A and 21 patients (30 nodules) were treated by PMCT-combined TACE as Group B. All patients underwent PMCT with single-electrode and one-point ablation. Paired t-test was used to analyze pre- and postoperatively the volume of tumor and the necrosis volume after PMCT. Independent t-test was used to compare the difference in the necrosis area between two groups (α=0.05). Results All patients underwent PMCT or PMCT combined with TACE successfully. The tumor and necrosis size of Group A was 16.29±19.23 cm3 and 17.98±18.49 cm3 (P=0.650), and 11.95±12.78 cm3 and 16.60±11.70 cm3 of Group B (P=0.017). There was no significant difference on necrosis volume between the two groups (P=0.581). The necrosis area of Group B was larger than the size of the tumor (P=0.017), but the ablation area of the two groups was smaller than the theoretic area (P=0.001). (The theoretic area means that the necrosis area of ablation should be 1.0 cm larger than the tumor in diameter.) Conclusion PMCT combined with TACE could enlarge the ablation area, but will not lead to an ideal necrosis area than the PMCT alone. The lipiodol deposition in the tumor lesion may hinder the expansion of the heating field. Therefore, further research was needed.
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Affiliation(s)
- HongLiang Sun
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Department of Radiology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - JiaYan Ni
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - XiongYing Jiang
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Dong Chen
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - YaoTing Chen
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - LinFeng Xu
- Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
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Kolluri SK, Jin UH, Safe S. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol 2017; 91:2497-2513. [PMID: 28508231 PMCID: PMC6357772 DOI: 10.1007/s00204-017-1981-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 05/08/2017] [Indexed: 12/31/2022]
Abstract
The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites. It has also been shown that like other receptors, the AhR is a drug target for multiple diseases including cancer, where both AhR agonists and antagonists effectively block many of the critical hallmarks of cancer in multiple tumor types. This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy.
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Affiliation(s)
- Siva Kumar Kolluri
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA
| | - Un-Ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A & M University, 4466 TAMU, College Station, TX, 77843, USA
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A & M University, 4466 TAMU, College Station, TX, 77843, USA.
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Takeda H, Nishikawa H, Osaki Y, Tsuchiya K, Joko K, Ogawa C, Taniguchi H, Orito E, Uchida Y, Izumi N. Proposal of Japan Red Cross score for sorafenib therapy in hepatocellular carcinoma. Hepatol Res 2015; 45:E130-40. [PMID: 25581351 DOI: 10.1111/hepr.12480] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 12/22/2014] [Accepted: 01/04/2015] [Indexed: 12/22/2022]
Abstract
AIM There have been no established predictors of the outcome on sorafenib therapy for hepatocellular carcinoma (HCC) patients. We aimed to establish a new prognostic model suitable for sorafenib in HCC. METHODS Among 465 HCC patients treated with sorafenib in 14 hospitals, we formed a training cohort with 270 patients at seven hospitals located in West Japan and a validation cohort with 167 patients at seven hospitals located in East Japan. In the training cohort, we examined the relationship between overall survival (OS) and pretreatment clinical factors, and structured a new prognostic model. We verified this model in the validation cohort and compared with four existing staging models. RESULTS Multivariate analysis demonstrated distant metastases, portal invasion, intrahepatic tumor burden of more than 50%, serum α-fetoprotein of 150 ng/dL or more, des-γ-carboxyprothrombin of 1200 mAU/mL or more, albumin of 3.5 g/dL or less and total bilirubin of more than 1.0 mg/dL were significant independent adverse prognostic factors. We calculated a Japan Red Cross (JRC) score with these factors and classified three groups: low-, intermediate- or high-risk. Their median OS were well stratified (18.0, 8.8 and 3.7 months, respectively, P < 0.001) in the training cohort. In the validation cohort, OS were also statistically stratified (23.9, 10.3 and 2.9 months, P < 0.001). C-statistics of the JRC score was 0.755, the highest in the five models, indicating its novel predictability. CONCLUSION Our proposed JRC score well predicts the prognosis of sorafenib therapy, and would be useful to plan individualized strategies for unresectable HCC.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Hiroyoshi Taniguchi
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Etsuro Orito
- Department of Gastroenterology and Hepatology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
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Sacco R, Mismas V, Romano A, Bertini M, Bertoni M, Federici G, Metrangolo S, Parisi G, Tumino E, Bresci G, Giacomelli L, Marceglia S, Bargellini I. Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients. World J Hepatol 2015; 7:33-39. [PMID: 25624994 PMCID: PMC4295191 DOI: 10.4254/wjh.v7.i1.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/10/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.
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