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Anticarin-β shows a promising antiosteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

Acta Pharmaceutica Sinica B 2022年第5期12卷 2268-2279页

作者： Gan Wang Min Zhang Ping Meng Chengbo Long Xiaodong Luo Xingwei Yang Yunfei Wang Zhiye Zhang James Mwangi Peter Muiruri Kamau Zhi Daic Zunfu Ke Yi Zhang Wenlin Chen Xudong Zhao Fei Ge Qiumin Lv Mingqiang Rong Dongsheng Li Yang Jin Xia Sheng Ren Lai Key Laboratory of Animal models and Human Disease Mechanisms Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan ProvinceKIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesNational Resource Center for Non-Human PrimatesKunming Primate Research Centerand National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyKunming 650107China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunming 650201China Institutes for Drug Discovery and Development Chinese Academy of SciencesShanghai 201203China Sino-African Joint Research Center Chinese Academy of ScienceWuhan 430074China Department of Pathology First Afﬁliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Orthopaedic Surgery First Afﬁliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Breast Surgery Third Afﬁliated Hospital of Kunming Medical UniversityYunnan Cancer CenterKunming 650118China Department of Breast Surgery First Afﬁliated Hospital of Kunming Medical UniversityKunming 650032China Department of Biosciences University of OsloOslo 0316Norway Key Laboratory of Environment and Health Ministry of Education&Ministry of Environmental ProtectionAnd State Key Laboratory of Environmental HealthSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 434000China Center for Biosafety Mega-Science Chinese Academy of SciencesWuhan 430071China

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

关键词： Proteostasis CCT TRiC Osteosarcoma STAT3 Anticarin-β pdx model

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Synergetic delivery of triptolide and Ce6 with light-activatable liposomes for efficient hepatocellular carcinoma therapy

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Acta Pharmaceutica Sinica B 2021年第7期11卷 2004-2015页

作者： Ling Yu Zhenjie Wang Zhuomao Mo Binhua Zou Yuanyuan Yang Rui Sun Wen Ma Meng Yu Shijun Zhang Zhiqiang Yu Department of Traditional Chinese Medicine the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China The People’s Hospital of Gaozhou Maoming 525200China School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of New Drug ScreeningSouthern Medical UniversityGuangzhou 510515China

Hepatocellular carcinoma(HCC)has been known as the second common leading cancer worldwide,as it responds poorly to both chemotherapy and medication.Triptolide(TP),a diterpenoid triepoxide,is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC.However,its clinical application has been limited owing to its severe systemic toxicities,low solubility,and fast elimination in the body.Therefore,to overcome the above obstacles,photo-activatable liposomes(LP)integrated with both photosensitizer Ce6 and chemotherapeutic drug TP(TP/Ce6-LP)was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy.The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention(EPR)effect.Under laser irradiation,the photosensitizer Ce6 generated reactive oxygen species(ROS)and further oxidized the unsaturated phospholipids.In this way,the liposomes were destroyed to release TP.TP/Ce6-LP with NIR laser irradiation(TP/Ce6-LP+L)showed the best antitumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC(pdxHCC).TP/Ce6-LP significantly reduced the side effects of TP.Furthermore,TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway.Overall,TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity.

关键词： Hepatocellular carcinoma Synergetic delivery Triptolide Ce6 Photo-activatable liposomes Photosensitizer Process of photodynamic therapy pdx model

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A Review of Progress in the Construction and Application of Human-Derived Xenograft models for Bladder Cancer

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Journal of Biosciences and Medicines 2022年第2期10卷 27-38页

作者： Hao Huang Qi Zhao Chen Gong Xiaowu Pi Feng Guo Jun Li Ying Xiong The First Affiliated Hospital of Yangtze University Jingzhou China

The patient-derived xenografts (pdx) model is an animal model established by transplanting primary tumors or fresh tumor tissues of patient origin directly into immunodeficient mice, which preserves the heterogeneity and survival microenvironment of the primary tumor and is widely used in preclinical and precision medicine research of tumors. This article reviews the construction of the pdx model of human bladder cancer and the progress of the application of the pdx model in bladder cancer.

关键词： Bladder Cancer pdx model Tumor Transplantation Preclinical Study

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