Identification of anti-malarial compounds as novel antagonists to chemokine receptor CXCR4 in pancreatic cancer cells.
Identification of anti-malarial compounds as novel antagonists to chemokine receptor CXCR4 in pancreatic cancer cells.
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DOI：
10.1371/journal.pone.0031004
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Vaidehi N
中科院分区：
文献类型：
--
作者：
Kim J;Yip ML;Shen X;Li H;Hsin LY;Labarge S;Heinrich EL;Lee W;Lu J;Vaidehi N
尽管最近在靶向治疗方面取得了进展，但胰腺癌患者的生存率仍然很低，这突出了确定新的治疗靶点的紧迫性。我们以前的研究表明趋化因子受体CXCR 4及其选择性配体CXCL 12参与了胰腺上皮内瘤变和浸润性胰腺癌的发病机制和进展;因此，CXCR 4是抑制胰腺癌生长的有希望的靶点。在这里，我们结合了CXCR 4的计算机结构建模，通过体外细胞系测定筛选候选抗CXCR 4化合物，并从美国国家癌症研究所（NCI）开放化学库收藏中鉴定出NSC 56612作为活化CXCR 4的抑制剂。接下来，我们发现NSC 56612在结构上与已知的抗疟疾药物氯喹和羟氯喹相似。我们在体外胰腺癌细胞中评估了这些化合物，并观察到CXCR 4介导的信号传导和细胞增殖的特异性拮抗作用。最近氯喹在胰腺癌小鼠模型中的体内治疗应用已经证明了降低肿瘤生长和改善存活率。因此，我们的研究结果提供了一个分子靶点和基础，进一步评估氯喹和羟氯喹在胰腺癌。历史上，氯喹和羟氯喹在人类中是安全的，似乎是安全有效地靶向胰腺癌患者CXCR 4的有希望的药物。
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.
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
15
作者：
Bhattacharya, Supriyo;Vaidehi, Nagarajan
通讯作者：
Vaidehi, Nagarajan
影响因子：
5.6
作者：
Lam, Alfonso R.;Bhattacharya, Supriyo;Vaidehi, Nagarajan
通讯作者：
Vaidehi, Nagarajan
DOI：
10.1124/jpet.301.3.1179
发表时间：
2002-06-01
影响因子：
3.5
作者：
Kilts, JD;Connery, HS;Mailman, RB
通讯作者：
Mailman, RB
影响因子：
3.2
作者：
Heo, Jiyoung;Han, Sang-Kyou;Goddard, William A., III
通讯作者：
Goddard, William A., III