The anticancer effect of PQ1 in the MMTV-PyVT mouse model.
The anticancer effect of PQ1 in the MMTV-PyVT mouse model.
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DOI：
10.1002/ijc.28461
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发表时间：
2014-03-15
影响因子：
6.4
通讯作者：
Thu Annelise Nguyen
中科院分区：
文献类型：
--
作者：
Shishido, Stephanie N.;Delahaye, Adelaide;Beck, Amanda;Thu Annelise Nguyen
动物模型常用于分析致癌机制以及开发和筛选强效药物。在此，使用转基因株FVB/N-Tg（MMTV-PyVT）634 Mul/J（也称为PyVT）作为用于测量乳腺癌的肿瘤负荷、药物敏感性和转移的模型系统。细胞间隙连接通讯的丧失和连接蛋白表达的下调是肿瘤细胞的特征。取代的喹啉，6-甲氧基-8-[（3-氨基丙基）氨基]-4-甲基-5-（3-三氟甲基-苯氧基）喹诺酮（PQ 1），已被证明可以恢复GJIC并增加乳腺癌细胞系中的连接蛋白表达，同时不影响正常乳腺细胞，这表明它可以提供具有较少有害作用的有效抗癌治疗。使用PyVT自发性乳腺肿瘤小鼠模型来确定PQ 1在三个发展阶段对肿瘤发生和转移的生物学和组织学作用：肿瘤前、早期肿瘤和晚期肿瘤形成。在所有三个发育阶段用PQ 1治疗显著降低了肿瘤生长。PQ 1治疗进一步增加了Cx43在前和早期肿瘤形成过程中的表达，而它阻止了Cx46在晚期肿瘤形成过程中表达的增加。这项研究表明，Cx43表达和肿瘤细胞生长呈负相关，但PQ 1可以通过靶向间隙连接蛋白改变肿瘤生长，以证明在治疗自发性乳腺肿瘤中的临床疗效。
Animal models are commonly used to analyze the mechanism of carcinogenesis as well as the development and screening of potent drugs. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden, drug sensitivity, and metastasis of mammary carcinomas. Loss of gap junctional intercellular communication and the down regulation of connexin expression are characteristic of neoplastic cells. The substituted quinoline, 6-Methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethyl-phenyloxy)quinolone (PQ1), has been shown to restore GJIC and increase connexin expression in breast cancer cell lines while not affecting normal mammary cells, suggesting that it may provide effective anti-cancer treatment with less detrimental effects. The PyVT spontaneous mammary tumor mouse model was used to determine the biological and histological effects of PQ1 on tumorigenesis and metastasis at three stages of development: Pre-tumor, Early tumor, and Late tumor formation. Treatment with PQ1 at all three stages of development significantly reduced tumor growth. PQ1 treatment further increased Cx43 expression during Pre- and Early-tumor formation, while it prevented an increase in Cx46 expression during Late stage tumor formation. This study shows that Cx43 expression and neoplastic cellular growth are inversely related, but that PQ1 can alter tumor growth through targeting gap junction proteins to prove clinical efficacy in the treatment of spontaneous mammary tumors.
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