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1
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Tang J, Yang J, Yin LK. Prognostic value of disulfidptosis-associated genes in gastric cancer: a comprehensive analysis. Front Oncol 2025; 15:1512394. [PMID: 40104507 PMCID: PMC11913695 DOI: 10.3389/fonc.2025.1512394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/10/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Disulfidptosis is a newly identified type of nonapoptotic programmed cell death related to mechanisms such as ferroptosis, cuproptosis, pyroptosis, and necrotic apoptosis. This study explores the role of disulfidptosis-related long non-coding RNAs (DRLs) in gastric cancer and their potential as prognostic biomarkers. Method We developed a prognostic model using DRL scores to classify patients based on disulfidptosis activity. We evaluated these scores for correlations with drug sensitivity, tumor microenvironment (TME) features, tumor mutational burden (TMB), and prognosis. Potential disulfidptosis-related signaling pathways were screened, identifying FRMD6-AS as a promising therapeutic target. FRMD6-AS expression was further validated using real-time fluorescent quantitative PCR (qRT-PCR). Results The DRL-based prognostic model, established through univariate and multivariate Cox regression and LASSO regression analyses, outperformed traditional models in predicting prognosis. We divided samples into high-risk and low-risk groups based on DRL scores, finding that the low-risk group had a significantly higher survival rate (P < 0.05). A high-precision prediction model incorporating DRL scores, age, sex, grade, and stage showed strong predictive value and consistency with actual outcomes. High DRL scores correlated with higher TME scores and lower TMB. Key signaling axes identified were AC129507.1/(FLNA, TLN1)/FOCAL ADHESION and AC107021.2/MYH10/(TIGHT JUNCTION, VIRAL MYOCARDITIS, REGULATION OF ACTIN CYTOSKELETON). Potentially effective drugs, including BMS-754807, dabrafenib, and JQ1, were identified. FRMD6-AS emerged as a potential target for gastric cancer treatment. Conclusions This study developed a novel prognostic model for gastric cancer using DRLs, identifying two key signaling axes related to prognosis. JQ1 may be an effective treatment, and FRMD6-AS could be a promising therapeutic target.
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Affiliation(s)
- Jin Tang
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jing Yang
- Department of Rheumatology and Immunology, Nanchong Central Hospital, Beijing Anzhen Hospital affiliated to Capital Medical University, Nanchong, Sichuan, China
| | - Long-Kuan Yin
- Department of Gastrointestinal Surgery, People's Hospital of Fushun County, Zigong, Sichuan, China
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2
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Luo L, Xin X, Wang Q, Wei M, Huang N, Gao S, Gu X, Li R. Characterization and comparation of toxicity between natural realgar and artificially optimized realgar. Front Pharmacol 2024; 15:1476139. [PMID: 39529880 PMCID: PMC11550961 DOI: 10.3389/fphar.2024.1476139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/27/2024] [Indexed: 11/16/2024] Open
Abstract
Objective Realgar possesses important medical properties. This article aims to evaluate realgar and emerging artificially optimized realgar to ensure safe clinical use. Methods Multiple techniques were employed to test natural realgar and artificially optimized realgar. Soluble arsenic content in representative samples were measured. Natural realgar and artificially optimized realgar were administered to KM mice via gavage for 28 days, and the extent of liver and kidney tissue damage, arsenic accumulation and form of arsenic were measured. Results Natural realgar and artificially optimized realgar can be distinguished by their physical properties or spectral signatures. ICP-MS and EPMA identified different contents of elements between two groups. In simulated gastric and intestinal fluids, only As (III) and As (V) were detected. Toxicity experiments in vivo demonstrate that both groups caused minimal liver and kidney damage at a dose of 30 mg·kg-1. At a dose of 180 mg·kg-1, artificially optimized realgar caused significantly greater liver and kidney damage. Conclusion The differences between natural realgar and artificially optimized realgar were successfully distinguished through several methods. In vitro experiments showed that As is the main component exerting their medicinal effects. In vivo toxicity tests demonstrated that at higher dose, artificially optimized realgar exhibited significantly higher toxicity, suggesting that natural and artificially optimized realgar have different toxic properties.
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Affiliation(s)
- Lu Luo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xueying Xin
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiaochu Wang
- Departments of Oncology, Georgetown University, Washington, DC, United States
| | - Mengjia Wei
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Nanxi Huang
- Departments of Oncology, Georgetown University, Washington, DC, United States
| | - Shuangrong Gao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuezhu Gu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Raorao Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
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3
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Leite M, Seruca R, Gonçalves JM. Drug Repurposing in Gastric Cancer: Current Status and Future Perspectives. HEREDITARY GASTRIC AND BREAST CANCER SYNDROME 2023:281-320. [DOI: 10.1007/978-3-031-21317-5_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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4
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Pibiri M, Simbula G. Role of the Hippo pathway in liver regeneration and repair: recent advances. Inflamm Regen 2022; 42:59. [PMID: 36471376 PMCID: PMC9720992 DOI: 10.1186/s41232-022-00235-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/09/2022] [Indexed: 12/12/2022] Open
Abstract
Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.
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Affiliation(s)
- Monica Pibiri
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
| | - Gabriella Simbula
- grid.7763.50000 0004 1755 3242Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. Monserrato-Sestu km 0.700, Blocco A. 09042 Monserrato, Cagliari, Italy
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5
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Sun HY, Du ST, Li YY, Deng GT, Zeng FR. Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:75-89. [PMID: 35116104 PMCID: PMC8790409 DOI: 10.4251/wjgo.v14.i1.75] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/11/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.
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Affiliation(s)
- Hui-Yan Sun
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Song-Tao Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ya-Yun Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Tian W, Sun Y, Cheng Y, Ma X, Du W, Shi W, Guo Q. Arsenic sulfide reverses cisplatin resistance in non-small cell lung cancer in vitro and in vivo through targeting PD-L1. Thorac Cancer 2021; 12:2551-2563. [PMID: 34469060 PMCID: PMC8487818 DOI: 10.1111/1759-7714.14136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As4 S4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As4 S4 could reverse DDP resistance through targeting PD-L1 in NSCLC. METHODS The effect of As4 S4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. RESULTS Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As4 S4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As4 S4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As4 S4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As4 S4 and DDP in A549/DDP cells. Cotreatment of DDP and As4 S4 notably reduced the tumor size when compared with DDP treatment alone in vivo. CONCLUSIONS Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As4 S4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.
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Affiliation(s)
- Wei Tian
- Department of Respiratory Medicine Oncology Ward I, Shandong Cancer Hospital and Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Oncology III, Zibo Central Hospital, Zibo, China
| | - Yinping Sun
- Department of Oncology III, Zibo Central Hospital, Zibo, China
| | - Yuping Cheng
- Department of Oncology III, Zibo Central Hospital, Zibo, China
| | - Xiao Ma
- Department of Internal Medicine, Zhangqiu People's Hospital, Zhangqiu, China
| | - Weina Du
- Department of Critical Medicine, Huantai People's Hospital, Zibo, China
| | - Wenna Shi
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qisen Guo
- Department of Respiratory Medicine Oncology Ward I, Shandong Cancer Hospital and Institute, Cheeloo College of Medicine, Shandong University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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7
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Wang L, Zhang Y, Chen Y, Tan J, Wang L, Zhang J, Yang C, Ma Q, Ge Y, Xu Z, Pan Z, Du L, Yan F, Yao W, Zhang H. The Performance of a Dual-Energy CT Derived Radiomics Model in Differentiating Serosal Invasion for Advanced Gastric Cancer Patients After Neoadjuvant Chemotherapy: Iodine Map Combined With 120-kV Equivalent Mixed Images. Front Oncol 2021; 10:562945. [PMID: 33585186 PMCID: PMC7874026 DOI: 10.3389/fonc.2020.562945] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 11/23/2020] [Indexed: 12/26/2022] Open
Abstract
Objectives The aim was to determine whether the dual-energy CT radiomics model derived from an iodine map (IM) has incremental diagnostic value for the model based on 120-kV equivalent mixed images (120 kVp) in preoperative restaging of serosal invasion with locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy (NAC). Methods A total of 155 patients (110 in the training cohort and 45 in the testing cohort) with LAGC who had standard NAC before surgery were retrospectively enrolled. All CT images were analyzed by two radiologists for manual classification. Volumes of interests (VOIs) were delineated semi-automatically, and 1,226 radiomics features were extracted from every segmented lesion in both IM and 120 kVp images, respectively. Spearman's correlation analysis and the least absolute shrinkage and selection operator (LASSO) penalized logistic regression were implemented for filtering unstable and redundant features and screening out vital features. Two predictive models (120 kVp and IM-120 kVp) based on 120 kVp selected features only and 120 kVp combined with IM selected features were established by multivariate logistic regression analysis. We then build a combination model (ComModel) developed with IM-120 kVp signature and ycT. The performance of these three models and manual classification were evaluated and compared. Result Three radiomics models showed great predictive accuracy and performance in both the training and testing cohorts (ComModel: AUC: training, 0.953, testing, 0.914; IM-120 kVp: AUC: training, 0.953, testing, 0.879; 120 kVp: AUC: training, 0.940, testing, 0.831). All these models showed higher diagnostic accuracy (ComModel: 88.9%, IM-120 kVp: 84.4%, 120 kVp: 80.0%) than manual classification (68.9%) in the testing group. ComModel and IM-120 kVp model had better performances than manual classification both in the training (both p<0.001) and testing cohorts (p<0.001 and p=0.034, respectively). Conclusions Dual-energy CT-based radiomics models demonstrated convincible diagnostic performance in differentiating serosal invasion in preoperative restaging for LAGC. The radiomics features derived from IM showed great potential for improving the diagnostic capability.
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Affiliation(s)
- Lingyun Wang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Zhang
- Department of Radiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Yong Chen
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingwen Tan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lan Wang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxue Yang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianchen Ma
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingqian Ge
- CHN DI CT Collaboration, Siemens Healthineers Ltd, Shanghai, China
| | - Zhihan Xu
- CHN DI CT Collaboration, Siemens Healthineers Ltd, Shanghai, China
| | - Zilai Pan
- Department of Radiology, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lianjun Du
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwu Yao
- Department of Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huan Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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8
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Liu C, Miao X, Wang Y, Wen L, Cheng X, Kong D, Zhao P, Song D, Wang X, Ding X, Xia H, Wang W, Sun Q, Gong W. Bromo- and extraterminal domain protein inhibition improves immunotherapy efficacy in hepatocellular carcinoma. Cancer Sci 2020; 111:3503-3515. [PMID: 32726482 PMCID: PMC7540980 DOI: 10.1111/cas.14588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/13/2020] [Accepted: 07/17/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer-related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo- and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death-ligand 1 (PD-L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD-L1 on the plasma membrane. This study also showed that JQ1 combined with anti-PD-L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD-L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.
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Affiliation(s)
- Chen Liu
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Xiaolong Miao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Yao Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Liang Wen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiawei Cheng
- Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Deqiang Kong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Pengwei Zhao
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Dandan Song
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyi Wang
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Hongguang Xia
- Department of Biochemistry and Molecular Biology of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilin Wang
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
| | - Qiming Sun
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
| | - Weihua Gong
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China.,Cancer Center, Zhejiang University, Hangzhou, China
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9
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Sun M, Hua J, Liu G, Huang P, Liu N, He X. Myrrh induces the apoptosis and inhibits the proliferation and migration of gastric cancer cells through down-regulating cyclooxygenase-2 expression. Biosci Rep 2020; 40:BSR20192372. [PMID: 32364228 PMCID: PMC7240199 DOI: 10.1042/bsr20192372] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 03/31/2020] [Accepted: 04/30/2020] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE The present study is designed to evaluate the anti-tumor effects of myrrh on human gastric cancer both in vitro and in vivo. METHODS The gastric cancer cell proliferation was determined by MTT assay. Apoptosis was measured by flow cytometry and Hoechst 33342 staining. Wound healing was performed to evaluate the effects of myrrh on the migration. COX-2, PCNA, Bcl-2, and Bax expressions were detected by Western blot analysis. A xenograft nude mice model of human gastric cancer was established to evaluate the anti-cancer effect of myrrh in vivo. RESULTS Myrrh significantly inhibited cellular proliferation, migration, and induced apoptosis in vitro as well as inhibited tumor growth in vivo. In addition, myrrh inhibited the expression of PCNA, COX-2, and Bcl-2 as well as increased Bax expression in gastric cancer cells. CONCLUSION Myrrh may inhibit the proliferation and migration of gastric cancer cells, as well as induced their apoptosis by down-regulating the expression of COX-2.
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Affiliation(s)
- Mengxue Sun
- Department of Geriatrics, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China
| | - Jie Hua
- Department of Gastroenterology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China
| | - Gaoshuang Liu
- Department of Geriatrics, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China
| | - Peiyun Huang
- Department of Geriatrics, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China
| | - Ningsheng Liu
- Department of Pathology, Nanjing Medical University, Nanjing 210000, China
- The Key laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210000, China
| | - Xiaopu He
- Department of Geriatrics, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, China
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10
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Li H, Zhang J, Tong JHM, Chan AWH, Yu J, Kang W, To KF. Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors. Int J Mol Sci 2019; 20:ijms20235999. [PMID: 31795192 PMCID: PMC6929124 DOI: 10.3390/ijms20235999] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/23/2019] [Accepted: 11/25/2019] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a kind of solid tumor and the third most common cancer type in the world. It is a heterogeneous disease characterized by genetic and epigenetic aberrations. The TP53 mutation is the key step driving the transition from adenoma to adenocarcinoma. The functional roles of TP53 mutation in tumor development have been comprehensively investigated. In CRC, TP53 mutation was associated with poor prognosis and chemoresistance. A gain of function (GOF) of p53 mutants promotes cell proliferation, migration and invasion through multiple mechanisms. Restoring wild type p53 function, depleting p53 mutants, or intervention by targeting the oncogenic downstreams provides potential therapeutic strategies. In this review, we comprehensively summarize the GOF of p53 mutants in CRC progression as well as in some other solid tumors, and discuss the current strategies targeting p53 mutants in malignancies.
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Affiliation(s)
- Hui Li
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinglin Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Joanna Hung Man Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Anthony Wing Hung Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China;
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (W.K.); (K.F.T.); Tel.: +852-35051505 (W.K. & K.F.T.); Fax: +852-26497286 (W.K. & K.F.T.)
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; (H.L.); (J.Z.); (J.H.M.T.); (A.W.H.C.)
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: (W.K.); (K.F.T.); Tel.: +852-35051505 (W.K. & K.F.T.); Fax: +852-26497286 (W.K. & K.F.T.)
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Liu C, Cheng X, Chen J, Wang Y, Wu X, Tian R, Liu B, Ding X, Sun Q, Gong W. Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration. Am J Cancer Res 2019; 9:3840-3852. [PMID: 31281517 PMCID: PMC6587347 DOI: 10.7150/thno.33370] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/06/2019] [Indexed: 12/16/2022] Open
Abstract
Background and aims: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro. We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro. By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. Conclusion: These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.
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Xu J, Wang Q, Leung ELH, Li Y, Fan X, Wu Q, Yao X, Liu L. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer. Front Med 2019; 14:60-67. [PMID: 31104301 DOI: 10.1007/s11684-019-0694-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 03/13/2019] [Indexed: 12/12/2022]
Abstract
Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.
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Affiliation(s)
- Jiahui Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Qianqian Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Elaine Lai Han Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
- Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Shiyan, 236600, China
- Department of Thoracic Surgery, Guangzhou Institute of Respiratory Health and State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China
| | - Ying Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Xingxing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
| | - Xiaojun Yao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
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13
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Pan Y, Fei Q, Xiong P, Yang J, Zhang Z, Lin X, Pan M, Lu F, Huang H. Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1. Oncoimmunology 2019; 8:e1581529. [PMID: 31069140 PMCID: PMC6492971 DOI: 10.1080/2162402x.2019.1581529] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/29/2018] [Accepted: 02/06/2019] [Indexed: 12/19/2022] Open
Abstract
Human pancreatic ductal adenocarcinoma (PDAC) exhibits marginal responses to anti-PD-1/PD-L1 immunotherapy and its mechanism remains poorly understood. We have investigated the effect of anti-PD-L1 and c-Myc inhibition in PDAC. Using 87 patients with PDAC from our hospital database we found a significant correlation between the expression of PD-L1 and c-Myc. Moreover, the expression of both PD-L1 and c-Myc was associated with poor overall survival. In addition, we confirmed this finding with the PDAC patients in the TCGA database. Using several PDAC cell lines we demonstrated a significant correlation between the expression of PD-L1 and c-Myc. We also found that expression of PD-L1 correlated with high-grade histology. JQ1, an inhibitor of c-Myc inhibited PD-L1 expression and tumor growth. Using xenograft models, we demonstrated that the combination of JQ1 and anti-PD-L1 antibody exerted synergistic inhibition of PDAC growth. Our data demonstrated that the expression of PD-L1 and c-Myc may be helpful prognostic biomarkers, and their inhibition may potentially serve as an effective treatment for PDAC.
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Affiliation(s)
- Yu Pan
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Qinglin Fei
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Ping Xiong
- Department of obstetrics and gynecology, 900 Hospital of the Joint Logistics Team, Fuzhou, China
| | - Jianyang Yang
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Zheyang Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Xianchao Lin
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Minggui Pan
- Department of Oncology and Hematology and Division of Research, Kaiser Permanente, Santa Clara, CA, USA
| | - Fengchun Lu
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China
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Wang S, Zhang C, Li Y, Li P, Zhang D, Li C. Anti-liver cancer effect and the mechanism of arsenic sulfide in vitro and in vivo. Cancer Chemother Pharmacol 2018; 83:519-530. [PMID: 30542770 DOI: 10.1007/s00280-018-3755-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE This study aimed at investigating the anti-tumor effect of arsenic sulfide (As2S2) against liver cancer both in vivo and in vitro and to elucidate its underlying mechanisms. METHODS Cell viability of the human hepatocellular carcinoma cell lines SMMC-7721, BEL-7402, HepG2 were measured by CCK-8 assay. The effects of As2S2 on cell proliferation and apoptosis of SMMC-7721 cells were investigated using Calcein-AM and PI staining, Hoechst 33258 staining, crystal violet staining, and JC-1 staining. Cell cycle and Annexin V/PI assay were analyzed via flow cytometry. The expression of apoptosis-related proteins, phosphorylation of PI3K and AKT were detected by Western blotting. H22-bearing mice model was established to evaluate the anti-tumor effect of As2S2 in vivo. HE staining, PCNA was observed via immunohistochemistry, and TUNEL assay was used to assess the anti-proliferation and pro-apoptotic effects of As2S2. RESULTS As2S2 significantly inhibited the growth of human hepatoma cells SMMC-7721, BEL-7402 and HepG2. As2S2 inhibited cell proliferation effectively by inducing G0/G1 cell cycle arrest in SMMC-7721 cells. As2S2 could increase Bax/Bcl-2 ratio, decrease mitochondrial membrane potential, promote the release of cytochrome c, increase the levels of cleaved caspase-3 and PARP, indicating that As2S2 induced apoptosis in SMMC-7721 cells via mitochondrial-mediated apoptosis pathway. Further research showed that As2S2 inhibited the PI3K/AKT signaling pathway leading to apoptotic cell death. In addition, As2S2 significantly inhibited tumor growth in H22-bearing mice and induced apoptosis by deactivating PI3K/AKT pathway, which was consistent with the in vitro results. CONCLUSION These findings suggested that As2S2 could induce apoptosis of liver cancer cells in vitro and in vivo, which was related to PI3K/AKT-mediated mitochondrial pathway and may provide a novel promising therapeutic agent for liver cancer treatment.
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Affiliation(s)
- Shudan Wang
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Chao Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yumei Li
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Ping Li
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Dafang Zhang
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Chaoying Li
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, China.
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Tan Z, Zhang X, Kang T, Zhang L, Chen S. Arsenic sulfide amplifies JQ1 toxicity via mitochondrial pathway in gastric and colon cancer cells. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:3913-3927. [PMID: 30532520 PMCID: PMC6241694 DOI: 10.2147/dddt.s180976] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Purpose Gastric and colon cancers have been the leading causes of cancer mortality in the world with limited therapy. Small molecules binding to bromodomains of bromodomain-containing protein 4 (BRD4) exert strong antitumor activities against hematological malignancies, while generally have limited efficacy in advanced solid tumors. Here, we found that the bromodomain and extra-terminal (BET)-bromodomain inhibitor JQ1, when combined with arsenic sulfide (As4S4, abbreviated as AS), synergistically decreased the expression of nuclear factor of activated T-cells (NFATs) as well as the downstream oncogene c-Myc and largely induced cell apoptosis via mitochondrial pathway in gastric and colon cancer cell lines. Methods The synergistic cytotoxicity of AS and JQ1 in gastric and colon cancer cells was determined by MTT assay and verified by FACS assay. Western blot analysis and quantitative real-time PCR (qPCR) assay were used to detect the expression of NFATs and downstream apoptotic proteins. The mitochondrial transmembrane potential was determined by FACS assay, and the metastasis of cancer cells was detected by the wound-healing assay. Results AS and JQ1 synergistically induced cell apoptosis in gastric and colon cancer cells by downregulating NFATs and upregulating apoptotic proteins. Combination of AS and JQ1 was associated with the decreased mitochondrial transmembrane potential, the cytochrome c release, and the subsequent caspase-3 activation. Conclusion Thus, our data indicate that AS can effectively enhance the cytotoxicity of BET inhibitors in gastric and colon cancer cells through mitochondrial-mediated apoptosis induction.
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Affiliation(s)
- Zhen Tan
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,
| | - Xiuli Zhang
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,
| | - Lian Zhang
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,
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Gao X, Zhang Y, Yuan F, Ding B, Ma Q, Yang W, Yan J, Du L, Wang B, Yan F, Sedlmair M, Pan Z, Zhang H. Locally advanced gastric cancer: total iodine uptake to predict the response of primary lesion to neoadjuvant chemotherapy. J Cancer Res Clin Oncol 2018; 144:2207-2218. [PMID: 30094537 DOI: 10.1007/s00432-018-2728-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 07/30/2018] [Indexed: 12/22/2022]
Abstract
PURPOSE Pathologic response to neoadjuvant chemotherapy is a prognostic factor in many cancer types. However, the existing evaluative criteria are deficient. We sought to prospectively evaluate the total iodine uptake derived from dual-energy computed tomography (DECT) in predicting treatment efficacy and progression-free survival (PFS) time in gastric cancer after neoadjuvant chemotherapy. METHODS From October 2012 to December 2015, 44 patients with locally advanced gastric cancer were examined with DECT 1 week before and three cycles after neoadjuvant chemotherapy. The percentage changes in tumor area (%ΔS), diameter (%ΔD), and density (%ΔHU) were calculated to evaluate the WHO, RESCIST, and Choi criteria. The percentage changes in tumor volume (%ΔV) and total iodine uptake of portal phase (%ΔTIU-p) were also calculated to determine cut-off values by ROC curves. The correlation between the different criteria and histopathologic tumor regression grade (Becker score) or PFS were statistically analyzed. RESULTS Forty-four patients were divided into responders and non-responders according to 43.34% volume reduction (P = 0.002) and 63.87% (P = 0.002) TIU-p reduction, respectively. The %ΔTIU-p showed strong (r = 0.602, P = 0.000) and %ΔV showed moderate (r = 0.416, P = 0.005), while the WHO (r = 0.075, P = 0.627), RECIST (r = 0.270, P = 0.077) and Choi criteria (r = 0.238, P = 0.120) showed no correlation with the Becker score. The differences in PFS time between the responder and non-responder groups were significant according to %ΔTIU-p and Choi criteria (P = 0.001 and P = 0.013, respectively). CONCLUSIONS The TIU-p can help predict pathological regression in advanced gastric cancer patients after neoadjuvant chemotherapy. In addition, the %ΔTIU-p could be one of the potentially valuable predictive parameters of the PFS time.
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Affiliation(s)
- Xiaoyuan Gao
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Yang Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Bei Ding
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Qianchen Ma
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Wenjie Yang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Jing Yan
- Siemens Medical System, Shanghai, 201318, China
| | - Lianjun Du
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Baisong Wang
- Department of Biological Statistics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China
| | - Martin Sedlmair
- Computed Tomography Research and Development, Siemens Healthcare GmbH, Forchheim, Germany
| | - Zilai Pan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China.
| | - Huan Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, China.
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Abstract
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.
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Affiliation(s)
- Montserrat Pérez-Salvia
- a Cancer Epigenetics and Biology Program (PEBC) , Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Catalonia , Spain
| | - Manel Esteller
- a Cancer Epigenetics and Biology Program (PEBC) , Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona , Catalonia , Spain.,b Department of Physiological Sciences II, School of Medicine , University of Barcelona , Barcelona , Catalonia , Spain.,c Institució Catalana de Recerca i Estudis Avançats (ICREA) , Barcelona , Catalonia , Spain
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18
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Ding W, Tong Y, Zhang X, Pan M, Chen S. Study of Arsenic Sulfide in Solid Tumor Cells Reveals Regulation of Nuclear Factors of Activated T-cells by PML and p53. Sci Rep 2016; 6:19793. [PMID: 26795951 PMCID: PMC4726130 DOI: 10.1038/srep19793] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 12/18/2015] [Indexed: 11/09/2022] Open
Abstract
Arsenic sulfide (AS) has excellent cytotoxic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be explored. Here we show that AS and cyclosporine A (CsA) exerted synergistic inhibitory effect on cell growth and c-Myc expression in HCT116 cells. AS inhibited the expression of PML, c-Myc, NFATc1, NFATc3, and NFATc4, while stimulating the expression of p53 and NFATc2. Knockdown of PML reduced NFATc1, NFATc2, NFATc3 and NFATc4 expression while overexpression of p53 stimulated NFATc2-luciferase activity that was further augmented by AS by binding to a set of p53 responsive elements (PREs) on the NFATc2 promoter. Additionally, overexpression of p53 suppressed NFATc3 and NFATc4. Reciprocally, NFATc3 knockdown enhanced p53 while reducing MDM2 expression indicating that NFATc3 is a negative regulator of p53 while a positive regulator of MDM2, consistent with its tumor-promoting property as knockdown of NFATc3 retarded cell growth in vitro and tumor growth in xenograft. In patients with colon cancer, tumor expression of NFATc2 correlated with superior survival, while nuclear NFATc1 with inferior survival. These results indicate that AS differentially regulates NFAT pathway through PML and p53 and reveal an intricate reciprocal regulatory relationship between NFAT proteins and p53 pathway.
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Affiliation(s)
- Wenping Ding
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingying Tong
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiuli Zhang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minggui Pan
- Department of Oncology and Hematology, Kaiser Permanente Medical Center, Santa Clara, CA.,Kaiser Permanente Division of Research, Oakland, CA, USA
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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