Reduction of the putative CD44+CD24- breast cancer stem cell population by targeting the polyamine metabolic pathway with PG11047
Reduction of the putative CD44+CD24- breast cancer stem cell population by targeting the polyamine metabolic pathway with PG11047
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DOI：
10.1097/cad.0b013e32833f2f77
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发表时间：
2010-11-01
影响因子：
2.3
通讯作者：
Oredsson, Stina M.
中科院分区：
文献类型：
--
作者：
Cirenajwis, Helena;Smiljanic, Sandra;Oredsson, Stina M.
癌症干细胞（CSC）被认为在癌症中特别受关注，因为它们具有自我更新和分化的固有特性，沿着表达与间充质表型相关的某些基因。这些特征有利于促进癌症患者的肿瘤复发和转移。因此，最佳的化疗治疗应该靶向CSC群体，通过杀死这些细胞和/或通过诱导它们转变为更分化的上皮样表型。对曲妥珠单抗耐药人表皮生长因子受体2过表达乳腺癌细胞系JIMT-1进行实验，以阐明多胺类似物[N-1，N-12]双（乙基）-顺式-6，7-脱氢精胺（PG 11047）和多胺生物合成抑制剂2-二氟甲基鸟氨酸（DFMO）对CD 44（+）CD 24（-）CSC群体的化疗作用。此外，还研究了对自我更新和上皮/间充质标志物的性质的影响。用PG 11047处理使JIMT-1细胞的CD 44（+）CD 24（-）亚群减少约50%，抑制和/或降低CSC群体的自我更新能力，降低细胞运动性并诱导参与促进上皮表型的间充质至上皮转化相关蛋白的表达。相比之下，DFMO略微增加了CD 44（+）CD 24（-）亚群，增加了细胞运动性和间充质相关蛋白的水平。DFMO治疗降低了CSC群体的自我更新能力。PG 11047和DFMO均降低人表皮生长因子受体2蛋白的表达，该蛋白与JIMT-1细胞中的恶性肿瘤和对曲妥珠单抗的耐药性相关。我们的研究结果表明，PG 11047治疗通过干扰几种干细胞相关特性，如自我更新，分化，运动和间充质表型，靶向CSC群体。Anti-Cancer Drugs 21：897-906（C）2010 Wolters Kluwer Health垂直栏Lippincott威廉姆斯& Wilkins.
Cancer stem cells (CSCs) are considered to be of particular concern in cancer as they possess inherent properties of self-renewal and differentiation, along with expressing certain genes related to a mesenchymal phenotype. These features favour the promotion of tumour recurrence and metastasis in cancer patients. Thus, the optimal chemotherapeutic treatment should target the CSC population, either by killing these cells and/or by inducing their transition to a more differentiated epithelial-like phenotype. Experiments were carried out on the trastuzumab-resistant human epidermal growth factor receptor 2-overexpressing breast cancer cell line JIMT-1 to unravel the chemotherapeutic effects of the polyamine analogue [N-1, N-12]bis(ethyl)-cis-6,7-dehydrospermine (PG11047) and of the polyamine biosynthetic inhibitor 2-difluoromethylornithine (DFMO) on the CD44(+)CD24(-) CSC population. Furthermore, effects on the properties of self-renewal and epithelial/mesenchymal markers were also investigated. Treatment with PG11047 reduced the CD44(+)CD24(-) subpopulation of JIMT-1 cells by approximately 50%, inhibited and/or reduced self-renewal capability of the CSC population, decreased cell motility and induced expression of mesenchymal to epithelial transition-associated proteins that are involved in promoting an epithelial phenotype. By contrast, DFMO slightly increased the CD44(+)CD24(-) subpopulation, increased cell motility and the level of mesenchymal-related proteins. DFMO treatment reduced the self-renewal capability of the CSC population. Both PG11047 and DFMO reduced the expression of the human epidermal growth factor receptor 2 protein, which is correlated to malignancy and resistance to trastuzumab in JIMT-1 cells. Our findings indicate that treatment with PG11047 targeted the CSC population by interfering with several stem cell-related properties, such as self-renewal, differentiation, motility and the mesenchymal phenotype. Anti-Cancer Drugs 21: 897-906 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.