32 results on '"Chen, Zhe-Sheng"'
Search Results
2. Characterization of the Nucleus Pulposus Progenitor Cells via Spatial Transcriptomics.
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Chen, Yu, Zhang, Long, Shi, Xueqing, Han, Jie, Chen, Jingyu, Zhang, Xinya, Xie, Danlin, Li, Zan, Niu, Xing, Chen, Lijie, Yang, Chaoyong, Sun, Xiujie, Zhou, Taifeng, Su, Peiqiang, Li, Na, Greenblatt, Matthew B., Ke, Rongqin, Huang, Jianming, Chen, Zhe‐Sheng, and Xu, Ren
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NUCLEUS pulposus ,PROGENITOR cells ,FATE mapping (Genetics) ,TRANSCRIPTOMES ,INTERVERTEBRAL disk - Abstract
Loss of refreshment in nucleus pulposus (NP) cellularity leads to intervertebral disc (IVD) degeneration. Nevertheless, the cellular sequence of NP cell differentiation remains unclear, although an increasing body of literature has identified markers of NP progenitor cells (NPPCs). Notably, due to their fragility, the physical enrichment of NP‐derived cells has limited conventional transcriptomic approaches in multiple studies. To overcome this limitation, a spatially resolved transcriptional atlas of the mouse IVD is generated via the 10x Genomics Visium platform dividing NP spots into two clusters. Based on this, most reported NPPC‐markers, including Cathepsin K (Ctsk), are rare and predominantly located within the NP‐outer subset. Cell lineage tracing further evidence that a small number of Ctsk‐expressing cells generate the entire adult NP tissue. In contrast, Tie2, which has long suggested labeling NPPCs, is actually neither expressed in NP subsets nor labels NPPCs and their descendants in mouse models; consistent with this, an in situ sequencing (ISS) analysis validated the absence of Tie2 in NP tissue. Similarly, no Tie2‐cre‐mediated labeling of NPPCs is observed in an IVD degenerative mouse model. Altogether, in this study, the first spatial transcriptomic map of the IVD is established, thereby providing a public resource for bone biology. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR‐27b‐3p targeting the SIK1‐CREB1 axis.
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Xiao, Ying‐Ying, Xia, Luo‐Xing, Jiang, Wen‐Jing, Qin, Jian‐Feng, Zhao, Li‐Xin, Li, Zhan, Huang, Li‐Juan, Li, Ke‐Xin, Yu, Peng‐Jiu, Wei, Li, Jiang, Xue‐Yan, Chen, Zhe‐Sheng, and Yu, Xi‐Yong
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MICRORNA ,EXOSOMES ,CARDIOPULMONARY system ,HEART ,MYOCARDIAL ischemia ,CORONARY disease - Abstract
Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA‐seq, flow cytometry, quantitative reverse transcription‐polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs‐Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA‐seq, bulk RNA‐seq, and bioinformatic approaches, and found the highly expressed miR‐27b‐3p in CPPs‐Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1‐CREB1 axis via exosomal miR‐27b‐3p. Our study offers a novel insight into the role of CPPs‐Exo in heart repair and highlights the potential of CPPs‐Exo as a promising therapeutic strategy for MI. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single‐Cell Transcriptomics.
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Zhang, Xin, Liang, Boxuan, Huang, Yuji, Meng, Hao, Li, Zhiming, Du, Jiaxin, Zhou, Lang, Zhong, Yizhou, Wang, Bo, Lin, Xi, Yu, Guangchuang, Chen, Xuewei, Lu, Weixiang, Chen, Zhe‐Sheng, Yang, Xingfen, and Huang, Zhenlie
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ANGIOTENSIN II ,MONONUCLEAR leukocytes ,TRANSCRIPTOMES ,GRANZYMES ,ANGIOTENSIN receptors ,ADENOCARCINOMA ,T cells ,FACADES ,PROGRAMMED cell death 1 receptors - Abstract
The increased use of low‐dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single‐cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin‐1 and angiotensin II receptor type 2 and a basal‐like molecular character. Furthermore, it identifies that cathepsin B+ tumor‐associated macrophages may over‐activate CD8+ T cells in MIA, leading to an enrichment of granzyme K+ senescent CD8+ T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients. [ABSTRACT FROM AUTHOR]
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- 2023
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5. MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance.
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Liu, Longyang, Chen, Chunlin, Liu, Ping, Li, Jing, Pang, Zhanjun, Zhu, Jiayu, Lin, Zhongqiu, Zhou, Haixu, Xie, Yingying, Lan, Tiancai, Chen, Zhe‐Sheng, Zeng, Zhaoyang, and Fang, Weiyi
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OVARIAN cancer ,DEUBIQUITINATING enzymes ,CISPLATIN ,CARCINOGENESIS ,PROTEIN domains ,GLUTATHIONE transferase ,MYOSIN - Abstract
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non‐muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co‐immunoprecipitation, GST pull‐down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non‐muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin‐specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co‐expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10‐MYH9‐snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Discovery of Norbornene as a Novel Hydrophobic Tag Applied in Protein Degradation.
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Xie, Shaowen, Zhan, Feiyan, Zhu, Jingjie, Sun, Yuan, Zhu, Huajian, Liu, Jie, Chen, Jian, Zhu, Zheying, Yang, Dong‐Hua, Chen, Zhe‐Sheng, Yao, Hong, Xu, Jinyi, and Xu, Shengtao
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PROTEOLYSIS ,ANAPLASTIC lymphoma kinase ,CHIMERIC proteins - Abstract
Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt‐9, potently reduced ALK levels through Hsp70 and the ubiquitin−proteasome system (UPS) in vitro without compensatory upregulation of ALK. Furthermore, Hyt‐9 exhibited a significant tumor‐inhibiting effect in vivo with moderate oral bioavailability. More importantly, norbornene can also be used to degrade the intractable enhancer of zeste homolog 2 (EZH2) when tagged with the EZH2 inhibitor tazemetostat. Thus, the discovery of novel hydrophobic norbornene tags shows promise for the future development of TPD technology. [ABSTRACT FROM AUTHOR]
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- 2023
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7. The Single‐Cell Landscape of Intratumoral Heterogeneity and The Immunosuppressive Microenvironment in Liver and Brain Metastases of Breast Cancer.
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Zou, Yutian, Ye, Feng, Kong, Yanan, Hu, Xiaoqian, Deng, Xinpei, Xie, Jindong, Song, Cailu, Ou, Xueqi, Wu, Song, Wu, Linyu, Xie, Yi, Tian, Wenwen, Tang, Yuhui, Wong, Chau‐Wei, Chen, Zhe‐Sheng, Xie, Xinhua, and Tang, Hailin
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METASTATIC breast cancer ,BRAIN metastasis ,IMMUNE checkpoint proteins ,REGULATORY T cells ,FIBROBLASTS ,LIVER cancer - Abstract
Distant metastasis remains the major cause of morbidity for breast cancer. Individuals with liver or brain metastasis have an extremely poor prognosis and low response rates to anti‐PD‐1/L1 immune checkpoint therapy compared to those with metastasis at other sites. Therefore, it is urgent to investigate the underlying mechanism of anti‐PD‐1/L1 resistance and develop more effective immunotherapy strategies for these patients. Using single‐cell RNA sequencing, a high‐resolution map of the entire tumor ecosystem based on 44 473 cells from breast cancer liver and brain metastases is depicted. Identified by canonical markers and confirmed by multiplex immunofluorescent staining, the metastatic ecosystem features remarkable reprogramming of immunosuppressive cells such as FOXP3+ regulatory T cells, LAMP3+ tolerogenic dendritic cells, CCL18+ M2‐like macrophages, RGS5+ cancer‐associated fibroblasts, and LGALS1+ microglial cells. In addition, PD‐1 and PD‐L1/2 are barely expressed in CD8+ T cells and cancer/immune/stromal cells, respectively. Interactions of the immune checkpoint molecules LAG3‐LGALS3 and TIGIT‐NECTIN2 between CD8+ T cells and cancer/immune/stromal cells are found to play dominant roles in the immune escape. In summary, this study dissects the intratumoral heterogeneity and immunosuppressive microenvironment in liver and brain metastases of breast cancer for the first time, providing insights into the most appropriate immunotherapy strategies for these patients. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Stellettin B Sensitizes Glioblastoma to DNA‐Damaging Treatments by Suppressing PI3K‐Mediated Homologous Recombination Repair.
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Peng, Xin, Zhang, Shaolu, Wang, Yingying, Zhou, Zhicheng, Yu, Zixiang, Zhong, Zhenxing, Zhang, Liang, Chen, Zhe‐Sheng, Claret, Francois X., Elkabets, Moshe, Wang, Feng, Sun, Fan, Wang, Ran, Liang, Han, Lin, Hou‐Wen, and Kong, Dexin
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GLIOBLASTOMA multiforme ,METHYLGUANINE ,TRITERPENES ,IONIZING radiation ,BLOOD-brain barrier ,CELL death ,DNA damage ,DNA repair ,TEMOZOLOMIDE - Abstract
Glioblastoma (GBM) is the most aggressive type of cancer. Its current first‐line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage‐inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA‐damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin‐proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood‐brain barrier to exert anti‐GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA‐damaging treatments. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications.
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Yang, Qiurong, Xu, Jing, Gu, Jianmei, Shi, Hui, Zhang, Jiayin, Zhang, Jianye, Chen, Zhe‐Sheng, Fang, Xinjian, Zhu, Taofeng, and Zhang, Xu
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EXTRACELLULAR vesicles ,DRUG resistance in cancer cells ,CANCER chemotherapy ,DRUG resistance ,CANCER cells ,TUMOR growth - Abstract
Extracellular vesicles (EVs) are cell‐derived nanosized vesicles that mediate cell‐to‐cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial‐mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Role of protein phosphorylation in cell signaling, disease, and the intervention therapy.
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Pang, Kun, Wang, Wei, Qin, Jia‐Xin, Shi, Zhen‐Duo, Hao, Lin, Ma, Yu‐Yang, Xu, Hao, Wu, Zhuo‐Xun, Pan, Deng, Chen, Zhe‐Sheng, and Han, Cong‐Hui
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PHOSPHOPROTEIN phosphatases ,CELL communication ,COMMUNICABLE diseases ,NEUROLOGY ,PROTEIN kinases - Abstract
Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development. [ABSTRACT FROM AUTHOR]
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- 2022
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11. The ethnomedicinal and functional uses, phytochemical and pharmacology of compounds from Ardisia species: An updated review.
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Liu, Bingrui, Liu, Rongyu, Liu, Qifeng, Ashby, Charles R., Zhang, Hang, and Chen, Zhe‐Sheng
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TRITERPENOID saponins ,SAPONINS ,SPECIES ,PHARMACOLOGY ,GONORRHEA ,MEDICINAL plants ,COUMARINS - Abstract
Medicinal plants are considered to be a critical source of novel compounds and pharmacophores. The genus Ardisia, consisting of approximately 500 species, is the largest genus in the Myrsinaceae family. Ardisia species are widely distributed throughout tropical and subtropical regions of the world and have been used for the treatment of cancer, hypertension, irregular menstruation, gonorrhea, diarrhea and postnatal syndromes, among others. Phytochemical studies of Ardisia species have resulted in the isolation and identification of 111 compounds, including triterpenoid saponins, quinones, phenols, coumarins, cyclic depsipepetide and flavonoids. Crude extracts and isolates from Ardisia have been reported to have in vitro and in vivo efficacies, including but not limited to anticancer, antiinflammatory, antimicrobial, antioxidant, antithrombotic and antidiabetic, antitubercular compounds. This review focuses on the medical and functional uses, phytochemical profile and pharmacological efficacies of Ardisia species over the past 15 years. This review will provide information indicating that Ardisia species represent an invaluable source of potential therapeutic compounds. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Fiber‐Optic Theranostics (FOT): Interstitial Fiber‐Optic Needles for Cancer Sensing and Therapy.
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Ran, Yang, Xu, Zhiyuan, Chen, Minfeng, Wang, Wei, Wu, Yang, Cai, Jiexuan, Long, Junqiu, Chen, Zhe‐Sheng, Zhang, Dongmei, and Guan, Bai‐Ou
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CANCER treatment ,COMPANION diagnostics ,PHOTOTHERMAL effect ,OPTICAL fibers ,FIBER optics - Abstract
Photonics has spurred a myriad of diagnostic and therapeutic applications for defeating cancer owing to its superiority in spatiotemporal maneuverability and minimal harm. The limits of light penetration depth and elusiveness of photosensitizer utilization, however, impede the implementation of the photodiagnostic and ‐therapy for determining and annihilating the deep‐situated tumor. Herein, a promising strategy that harnesses functional optical fibers is developed and demonstrated to realize an in vivo endoscopic cancer sensing and therapy ensemble. Tumor detection is investigated using hypoxia‐sensitive fluorescent fibers to realize fast and accurate tumor recognition and diagnosis. The tumor treatment is further performed by exploiting the endogenous photothermal effect of rare‐earth‐doped optical fibers. The eradication of orthotopic and subcutaneous xenografts significantly validates the availability of tumoricidal fibers. The strategy opens horizons to inspire the design of optical fiber‐mediated "plug and play" precise tumor theranostics with high safety, which may intrigue broader fields, such as fiber optics, materials, chemistry, medicine, and clinics. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Cycloruthenated Self‐Assembly with Metabolic Inhibition to Efficiently Overcome Multidrug Resistance in Cancers.
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Li, Jia, Zeng, Leli, Wang, Zheng, Chen, Hengxing, Fang, Shuo, Wang, Jinquan, Cai, Chao‐Yun, Xing, Enming, Liao, Xinxing, Li, Zhi‐Wei, Ashby, Charles R., Chen, Zhe‐Sheng, Chao, Hui, and Pan, Yihang
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- 2022
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14. ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates.
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Wang, Jing‐Quan, Wu, Zhuo‐Xun, Yang, Yuqi, Teng, Qiu‐Xu, Li, Yi‐Dong, Lei, Zi‐Ning, Jani, Khushboo A, Kaushal, Neeraj, and Chen, Zhe‐Sheng
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ATP-binding cassette transporters ,DRUG resistance in cancer cells ,MEMBRANE proteins ,MULTIDRUG resistance ,CELLULAR signal transduction - Abstract
The ATP‐binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross‐membrane transportation of various endo‐ and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure‐function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp).
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Zhang, Hang, Xu, Haiwei, Ashby, Charles R., Assaraf, Yehuda G., Chen, Zhe‐Sheng, and Liu, Hong‐Min
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MULTIDRUG resistance ,P-glycoprotein ,SMALL molecules ,CANCER chemotherapy ,ANTINEOPLASTIC agents ,STRUCTURE-activity relationships ,MULTIDRUG-resistant tuberculosis - Abstract
Multidrug resistance (MDR) remains one of the major impediments for efficacious cancer chemotherapy. Increased efflux of multiple chemotherapeutic drugs by transmembrane ATP‐binding cassette (ABC) transporter superfamily is considered one of the primary causes for cancer MDR, in which the role of P‐glycoprotein (P‐gp/ABCB1) has been most well‐established. The clinical co‐administration of P‐gp drug efflux inhibitors, in combination with anticancer drugs which are P‐gp transport substrates, was considered to be a treatment modality to surmount MDR in anticancer therapy by blocking P‐gp‐mediated multidrug efflux. Extensive attempts have been carried out to screen for sets of nontoxic, selective, and efficacious P‐gp efflux inhibitors. In this review, we highlight the recent achievements in drug design, characterization, structure–activity relationship (SAR) studies, and mechanisms of action of the newly synthetic, potent small molecules P‐gp inhibitors in the past 5 years. The development of P‐gp inhibitors will increase our knowledge of the mechanisms and functions of P‐gp‐mediated drug efflux which will benefit drug discovery and clinical cancer therapeutics where P‐gp transporter overexpression has been implicated in MDR. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells.
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Wu, Zhuo‐Xun, Yang, Yuqi, Wang, Guangsuo, Wang, Jing‐Quan, Teng, Qiu‐Xu, Sun, Lingling, Lei, Zi‐Ning, Lin, Lizhu, Chen, Zhe‐Sheng, and Zou, Chang
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One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR. [ABSTRACT FROM AUTHOR]
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- 2020
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17. Modulating the function of ABCB1: in vitro and in vivo characterization of sitravatinib, a tyrosine kinase inhibitor.
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Yang, Yuqi, Ji, Ning, Cai, Chao‐Yun, Wang, Jing‐Quan, Lei, Zi‐Ning, Teng, Qiu‐Xu, Wu, Zhuo‐Xun, Cui, Qingbin, Pan, Yihang, and Chen, Zhe‐Sheng
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- 2020
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18. GSK1904529A, a Potent IGF-IR Inhibitor, Reverses MRP1-Mediated Multidrug Resistance.
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Gupta, Pranav, Xie, Meina, Narayanan, Silpa, Wang, Yi‐Jun, Wang, Xiu‐Qi, Yuan, Timothy, Wang, Ziyue, Yang, Dong‐Hua, and Chen, Zhe‐Sheng
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- 2017
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19. 2-Trifluoromethyl-2-Hydroxypropionamide Derivatives as Novel Reversal Agents of ABCG2 (BCRP)-Mediated Multidrug Resistance: Synthesis and Biological Evaluations.
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Kathawala, Rishil J., Li, Tianwen, Yang, Danwen, Guo, Hui‐Qin, Yang, Dong‐Hua, Chen, Xiang, Cheng, Changmei, and Chen, Zhe‐Sheng
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- 2017
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20. Evodiamine Suppresses ABCG2 Mediated Drug Resistance by Inhibiting p50/p65 NF-κB Pathway in Colorectal Cancer.
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Sui, Hua, Zhou, Li‐Hong, Zhang, Ya‐Li, Huang, Jian‐Ping, Liu, Xuan, Ji, Qing, Fu, Xiao‐Ling, Wen, Hao‐Tian, Chen, Zhe‐Sheng, Deng, Wan‐Li, Zhu, Hui‐Rong, and Li, Qi
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- 2016
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21. In vitro, in vivo and ex vivo characterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1.
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Zhang, Hui, Patel, Atish, Ma, Shao ‐ Lin, Li, Xiao Jie, Zhang, Yun ‐ Kai, Yang, Pei ‐ Qi, Kathawala, Rishil J, Wang, Yi ‐ Jun, Anreddy, Nagaraju, Fu, Li ‐ Wu, and Chen, Zhe ‐ Sheng
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CARRIER proteins ,MULTIDRUG resistance ,ANTINEOPLASTIC agents ,IN vitro studies ,PROTEIN-tyrosine kinase inhibitors ,PROTEIN expression ,BIOACCUMULATION - Abstract
Background and Purpose The transporter, multidrug resistance protein 1 ( MRP1, ABCC1), plays a critical role in the development of multidrug resistance ( MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR. Experimental Approach Cytotoxicity was determined by MTT assay. The expression of protein was detected by Western blot. RT-PCR and Q-PCR were performed to detect the expression of MRP1 mRNA. The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293/ MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo. Key Results Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293/ MRP1 and HL60/ Adr cells overexpressing MRP1. Furthermore, ibrutinib increased the accumulation of substrates in these MRP1-overexpressing cells by inhibiting the drug efflux function of MRP1. However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1-overexpressing cells. In vivo, ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293/ MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. Conclusions and Implications Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1-overexpressing cells, in vitro, in vivo and ex vivo. These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1. [ABSTRACT FROM AUTHOR]
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- 2014
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22. ARRY-334543 Reverses Multidrug Resistance by Antagonizing the Activity of ATP-Binding Cassette Subfamily G Member 2.
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Wang, De‐Shen, Patel, Atish, Sim, Hong‐May, Zhang, Yun‐Kai, Wang, Yi‐Jun, Kathawala, Rishil J., Zhang, Hui, Talele, Tanaji T., Ambudkar, Suresh V., Xu, Rui‐Hua, and Chen, Zhe‐Sheng
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- 2014
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23. WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.
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Zhang, Hui, Zhang, Yun‐Kai, Wang, Yi‐Jun, Kathawala, Rishil J., Patel, Atish, Zhu, Hua, Sodani, Kamlesh, Talele, Tanaji T., Ambudkar, Suresh V., Chen, Zhe‐Sheng, and Fu, Li‐Wu
- Abstract
ATP-binding cassette ( ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function. [ABSTRACT FROM AUTHOR]
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- 2014
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24. Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.
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Liu, Ke‐Jun, He, Jie‐Hua, Su, Xiao‐Dong, Sim, Hong‐May, Xie, Jing‐Dun, Chen, Xing‐Gui, Wang, Fang, Liang, Yong‐Ju, Singh, Satyakam, Sodani, Kamlesh, Talele, Tanaji T., Ambudkar, Suresh V., Chen, Zhe‐Sheng, Wu, Hai‐Ying, and Fu, Li‐Wu
- Abstract
Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [
125 I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic. [ABSTRACT FROM AUTHOR]- Published
- 2013
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25. PDE5 inhibitors, sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux function of multidrug resistance protein 7 ( ATP-binding Cassette C10) transporter.
- Author
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Chen, Jun-Jiang, Sun, Yue-Li, Tiwari, Amit K., Xiao, Zhi-Jie, Sodani, Kamlesh, Yang, Dong-Hua, Vispute, Saraubh G., Jiang, Wen-Qi, Chen, Si-Dong, and Chen, Zhe-Sheng
- Abstract
Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and pulmonary hypertension. Recently, several groups have evaluated the ability of PDE5 inhibitors for their anticancer activities. Previously, we had shown that sildenafil, vardenafil and tadalafil could reverse P-glycoprotein ( ATP-binding cassette B1)-mediated MDR. In the present study, we determined whether these PDE5 inhibitors have the potential to reverse multidrug resistance protein 7 ( MRP7; ATP-binding cassette C10)-mediated MDR. We found that sildenafil and vardenafil dose-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine, while tadalafil had only a minimal effect. Accumulation and efflux experiments demonstrated that sildenafil and vardenafil increased the intracellular accumulation of [
3 H]-paclitaxel by inhibiting the efflux of [3 H]-paclitaxel in HEK/ MRP7 cells. In addition, immunoblot and immunofluorescence analyses indicated that no significant alterations of MRP7 protein expression and localization in plasma membranes were found after treatment with sildenafil, vardenafil or tadalafil. These results demonstrate that sildenafil and vardenafil reverse MRP7-mediated a MDR through inhibition of the drug efflux function of MRP7. Our findings indicate a potentially novel use of PDE5 inhibitors as an adjuvant chemotherapeutic agent in clinical practice. ( Cancer Sci 2012; 103: 1531-1537) [ABSTRACT FROM AUTHOR]- Published
- 2012
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26. Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases.
- Author
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Chen, Zhe-Sheng and Tiwari, Amit K.
- Subjects
- *
MULTIDRUG resistance , *CANCER chemotherapy , *GENETIC disorders , *ATP-binding cassette transporters , *MEMBRANE proteins , *HYDROLYSIS , *CANCER cells , *PSEUDOXANTHOMA elasticum - Abstract
The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that are best known for their ability to transport a wide variety of exogenous and endogenous substances across membranes against a concentration gradient via ATP hydrolysis. There are seven subfamilies of human ABC transporters, one of the largest being the 'C' subfamily (gene symbol ABCC). Nine ABCC subfamily members, the so-called multidrug resistance proteins (MRPs) 1-9, have been implicated in mediating multidrug resistance in tumor cells to varying degrees as the efflux extrude chemotherapeutic compounds (or their metabolites) from malignant cells. Some of the MRPs are also known to either influence drug disposition in normal tissues or modulate the elimination of drugs (or their metabolites) via hepatobiliary or renal excretory pathways. In addition, the cellular efflux of physiologically important organic anions such as leukotriene C4 and cAMP is mediated by one or more of the MRPs. Finally, mutations in several MRPs are associated with human genetic disorders. In this minireview, the current biochemical and physiological knowledge of MRP1-MRP9 in cancer chemotherapy and human genetic disease is summarized. The mutations in MRP2/ABCC2 leading to conjugated hyperbilirubinemia (Dubin-Johnson syndrome) and in MRP6/ABCC6 leading to the connective tissue disorder Pseudoxanthoma elasticum are also discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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- View/download PDF
27. Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.
- Author
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Shi, Zhi, Jain, Sandeep, Kim, In-Wha, Peng, Xing-Xiang, Abraham, Ioana, Youssef, Diaa T.A., Fu, Li-Wu, El Sayed, Khalid, Ambudkar, Suresh V., and Chen, Zhe-Sheng
- Abstract
Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. Sipholenol A (IC
50 > 50 µM) is not toxic to all the cell lines that were used, regardless of their membrane transporter status. Accumulation and efflux studies with the P-gp substrate [3 H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [3 H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not alter the expression of P-gp after treating KB-C2 and KB-V1 cells for 36 h and 72 h. However, it efficaciously stimulated the activity of ATPase of P-gp and inhibited the photolabeling of this transporter with its transport substrate [125 I]-iodoarylazidoprazosin. Overall, the present results indicate that sipholenol A efficiently inhibits the function of P-gp through direct interactions, and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp-overexpressing tumors. ( Cancer Sci 2007; 98: 1373–1380) [ABSTRACT FROM AUTHOR]- Published
- 2007
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- View/download PDF
28. Elevated expression of vacuolar proton pump genes and cellular ph in cisplatin resistance.
- Author
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Murakami, Tadashi, Shibuya, Izumi, Ise, Tomoko, Chen, Zhe-Sheng, Akiyama, Shin-ichi, Nakagawa, Masayuki, Izumi, Hiroto, Nakamura, Toshitaka, Matsuo, Ken-ichi, Yamada, Yuji, and Kohno, Kimitoshi
- Published
- 2001
- Full Text
- View/download PDF
29. Reversing Effect of Agosterol A, a Spongean Sterol Acetate, on Multidrug Resistance in Human Carcinoma Cells.
- Author
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Aoki, Shunji, Chen, Zhe-Sheng, Higasiyama, Kimihiko, Setiawan, I, Akiyama, Shin-ichi, and Kobayashi, Motomasa
- Published
- 2001
- Full Text
- View/download PDF
30. Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol a on MRP1 function.
- Author
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Chen, Zhe-Sheng, Aoki, Shunji, Komatsu, Masaharu, Ueda, Kazumitsu, Sumizawa, Tomoyuki, Furukawa, Tatsuhiko, Okumura, Hiroshi, Ren, Xiao-Qin, Belinsky, Martin G., Lee, Kun, Kruh, Gary D., Kobayashi, Motomasa, and Akiyama, Shin-ichi
- Published
- 2001
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31. Multidrug Resistance Reversal Activity of Taxoids from Taxus cuspidate in KB-C2 and 2780AD Cells.
- Author
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Kobayashi, Jun'ichi, Shigemori, Hideyuki, Hosoyama, Hirokazu, Chen, Zhe-Sheng, Akiyama, Shin-ichi, Naito, Mikihiko, and Tsuruo, Takashi
- Published
- 2000
- Full Text
- View/download PDF
32. ChemInform Abstract: New Phenstatin-Fatty Acid Conjugates: Synthesis and Evaluation.
- Author
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Chen, Jinhui, Brown, David P., Wang, Yi‐Jun, and Chen, Zhe‐Sheng
- Published
- 2014
- Full Text
- View/download PDF
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