Targeting NFκB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2
Targeting NFκB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2
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DOI：
10.4161/cbt.11.7.14903
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发表时间：
2011-04-01
影响因子：
3.6
通讯作者：
Beckman, Barbara S.
中科院分区：
文献类型：
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作者：
Antoon, James W.;White, Martin D.;Beckman, Barbara S.
对化疗的耐药性仍然是治疗非依赖性乳腺癌的一个重要障碍。最近的证据表明，通过增加鞘氨醇激酶活性改变鞘脂信号可能是乳腺癌耐药性的重要介导者。鞘氨醇激酶-1（Sphk 1）被认为是乳腺癌发生、增殖和耐药的关键调节因子。然而，关于鞘氨醇激酶-2（Sphk 2）在癌症生物学和耐药性中的作用存在相互矛盾的数据，有些人认为Sphk 2与Sphk 1具有相反的作用。在这里，我们研究了新型选择性Sphk 2抑制剂ABC 294640（3-（4-氯苯基）-金刚烷-1-羧酸（吡啶-4-基甲基）酰胺）对人乳腺癌的影响。ABC 294640在低微摩尔IC 50浓度下阻断内分泌治疗抗性MDA-MB-231和化学抗性MCF-7 TN-R细胞系统中的活力和存活。用抑制剂处理显著降低增殖，如在体外Ki-67的免疫荧光染色中所见。有趣的是，Sphk 2的药理学抑制通过内在程序性细胞死亡途径诱导细胞凋亡。此外，ABC 294640还通过降低p65亚基上Ser 536磷酸化位点的活化而减少NF κ B B存活信号传导。利用在免疫受损小鼠中生长的MCF-7 TN-R细胞的异种移植物来验证鞘氨醇激酶-2抑制剂的治疗功效。在该模型中，用50 mg ABC 294640/kg治疗完全阻断肿瘤体积。这些结果表明，口服生物可利用的选择性抑制剂ABC 294640对Sphk 2的药理学抑制在治疗化疗和内分泌治疗抗性乳腺癌中具有治疗潜力。
Resistance to chemotherapy remains a significant obstacle in the treatment of hormone-independent breast cancer. Recent evidence suggests that altered sphingolipid signaling through increased sphingosine kinase activity may be an important mediator of breast cancer drug resistance. Sphingosine kinase-1 (Sphk1) is a proposed key regulator of breast cancer tumorigenesis, proliferation and resistance. There is, however, conflicting data on the role of sphingosine kinase-2 (Sphk2) in cancer biology and resistance, with some suggesting that Sphk2 has an opposing role to that of Sphk1. Here, we studied the effects of the novel selective Sphk2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer. ABC294640 blocked both viability and survival at low micromolar IC50 concentrations in the endocrine therapy-resistant MDA-MB-231 and chemoresistant MCF-7TN-R cell systems. Treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, pharmacological inhibition of Sphk2 induced apoptosis through the intrinsic programmed cell death pathway. Furthermore, ABC294640 also diminished NF kappa B survival signaling, through decreased activation of the Ser536 phosphorylation site on the p65 subunit. Xenografts of MCF-7TN-R cells growing in immunocompromised mice were utilized to validate the therapeutic efficacy of the sphingosine kinase-2 inhibitor. Treatment with 50 mg of ABC294640/kg completely blocked tumor volume in this model. These results indicate that pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy-resistant breast cancer.