Identification of Anti-Malarial Compounds as Novel Antagonists to Chemokine Receptor CXCR4 in Pancreatic Cancer Cells

被引：57

作者：

Kim, Joseph ^{[1
]}

Yip, M. L. Richard ^{[2
]}

Shen, Xiaoming ^{[1
]}

Li, Hubert ^{[3
]}

Hsin, Li-Yu Charlie ^{[2
]}

Labarge, Samuel ^{[2
]}

Heinrich, Eileen L. ^{[1
]}

Lee, Wendy ^{[1
]}

Lu, Jianming ^{[1
]}

Vaidehi, Nagarajan ^{[3
]}

机构：

[1] City Hope Natl Med Ctr, Dept Surg, Duarte, CA USA

[2] City Hope Natl Med Ctr, Dept Mol Med, Duarte, CA USA

[3] City Hope Natl Med Ctr, Dept Immunol, Duarte, CA USA

来源：

PLOS ONE | 2012年 / 7卷 / 02期

基金：

美国国家卫生研究院;

关键词：

SMALL-MOLECULE; PLASMODIUM-FALCIPARUM; BETA-ARRESTIN; EXPRESSION; GEMCITABINE; CHLOROQUINE; AUTOPHAGY; BICYCLAM; SCREEN; PROLIFERATION;

D O I：

10.1371/journal.pone.0031004

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Despite recent advances in targeted therapies, patients with pancreatic adenocarcinoma continue to have poor survival highlighting the urgency to identify novel therapeutic targets. Our previous investigations have implicated chemokine receptor CXCR4 and its selective ligand CXCL12 in the pathogenesis and progression of pancreatic intraepithelial neoplasia and invasive pancreatic cancer; hence, CXCR4 is a promising target for suppression of pancreatic cancer growth. Here, we combined in silico structural modeling of CXCR4 to screen for candidate anti-CXCR4 compounds with in vitro cell line assays and identified NSC56612 from the National Cancer Institute's (NCI) Open Chemical Repository Collection as an inhibitor of activated CXCR4. Next, we identified that NSC56612 is structurally similar to the established anti-malarial drugs chloroquine and hydroxychloroquine. We evaluated these compounds in pancreatic cancer cells in vitro and observed specific antagonism of CXCR4-mediated signaling and cell proliferation. Recent in vivo therapeutic applications of chloroquine in pancreatic cancer mouse models have demonstrated decreased tumor growth and improved survival. Our results thus provide a molecular target and basis for further evaluation of chloroquine and hydroxychloroquine in pancreatic cancer. Historically safe in humans, chloroquine and hydroxychloroquine appear to be promising agents to safely and effectively target CXCR4 in patients with pancreatic cancer.

引用

页数：10

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