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Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C-82(OH)(22) and its implication for de novo design of nanomedicine
Kang, SG; Zhou GQ(周国强); Zhou, GQ; Yang, P; Liu, Y; Sun, BY; Huynh, T; Meng, H; Zhao, LN; Xing, GM; Chen, CY; Zhao, YL; Zhou, RH; Sun BY(孙宝云); Meng H(孟幻); Zhao LN(赵丽娜); Xing GM(邢更妹); Chen CY(陈春英); Zhao YL(赵宇亮)
2012
发表期刊PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷号109期号:38页码:15431-15436
摘要Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C-82(OH)(22) can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C-82(OH)(22) effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C-82(OH)(22) not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C-82(OH)(22)-MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C-82(OH)(22) inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C-82(OH)(22) exhibits specific binding modes near the ligand-specificity loop S1', thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific bindingmode make Gd@C-82(OH)(22) a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.
关键词indirect inhibition mode tumor metastasis antiangiogenesis inhibition of MMPs
学科领域Science & Technology - Other Topics
DOI10.1073/pnas.1204600109
收录类别SCI
WOS记录号WOS:000309211000073
引用统计
被引频次:120[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.ihep.ac.cn/handle/311005/224352
专题多学科研究中心
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GB/T 7714
Kang, SG,Zhou GQ,Zhou, GQ,et al. Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C-82(OH)(22) and its implication for de novo design of nanomedicine[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2012,109(38):15431-15436.
APA Kang, SG.,周国强.,Zhou, GQ.,Yang, P.,Liu, Y.,...&赵宇亮.(2012).Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C-82(OH)(22) and its implication for de novo design of nanomedicine.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,109(38),15431-15436.
MLA Kang, SG,et al."Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C-82(OH)(22) and its implication for de novo design of nanomedicine".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109.38(2012):15431-15436.
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