GSK-3 inhibition overcomes chemoresistance in human breast cancer.
GSK-3 inhibition overcomes chemoresistance in human breast cancer.
复制标题
GSK-3抑制克服了人类乳腺癌的化学抗性。
DOI：
10.1016/j.canlet.2016.07.006
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发表时间：
2016-10-01
期刊：
影响因子：
9.7
通讯作者：
Mazar AP
中科院分区：
文献类型：
--
作者：
Ugolkov A;Gaisina I;Zhang JS;Billadeau DD;White K;Kozikowski A;Jain S;Cristofanilli M;Giles F;O'Halloran T;Cryns VL;Mazar AP
糖原合成酶-3β(GSK-3β)是一种丝氨酸/苏氨酸蛋白激酶，是治疗乳腺癌的新靶点。在这项研究中，我们证明了两种新的小分子GSK-3抑制剂9-ING-41和9-ING-87对GSK-3的药理抑制作用，降低了乳腺癌细胞的活力，但对非致瘤细胞的生长几乎没有影响。此外，9-ING-41可增强伊立替康(CPT-11)对乳腺癌细胞的体外抗肿瘤作用。接下来，我们建立了两个患者来源的异种移植瘤模型(BC-1和BC-2)，该模型来自从进展性、化疗难治性乳腺癌患者获得的转移性胸腔积液，并证明9-ING-41还在体内增强了化疗药物CPT-11的作用，导致已建立的BC-1和BC-2肿瘤在小鼠体内消退。我们的结果表明，抑制GSK-3是克服乳腺癌化疗耐药的一种有前途的治疗方法，并将GSK-3抑制剂9-ING-41确定为转移性乳腺癌治疗的候选靶向药物。
Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine protein kinase, is an emerging therapeutic target in the treatment of human breast cancer. In this study, we demonstrate that the pharmacological inhibition of GSK-3 by two novel small molecule GSK-3 inhibitors, 9-ING-41 and 9-ING-87, reduced the viability of breast cancer cells but had little effect on non-tumorigenic cell growth. Moreover, treatment with 9-ING-41 enhanced the antitumor effect of irinotecan (CPT-11) against breast cancer cells in vitro. We next established two patient-derived xenograft tumor models (BC-1 and BC-2) from metastatic pleural effusions obtained from patients with progressive, chemorefractory breast cancer and demonstrated that 9-ING-41 also potentiated the effect of the chemotherapeutic drug CPT-11 in vivo, leading to regression of established BC-1 and BC-2 tumors in mice. Our results suggest that the inhibition of GSK-3 is a promising therapeutic approach to overcome chemoresistance in human breast cancer, and identify the GSK-3 inhibitor 9-ING-41 as a candidate targeted agent for metastatic breast cancer therapy.
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影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
5.7
作者：
Pal K;Cao Y;Gaisina IN;Bhattacharya S;Dutta SK;Wang E;Gunosewoyo H;Kozikowski AP;Billadeau DD;Mukhopadhyay D
通讯作者：
Mukhopadhyay D
影响因子：
11.2
作者：
Ougolkov, AV;Fernandez-Zapico, ME;Billadeau, DD
通讯作者：
Billadeau, DD
影响因子：
8
作者：
Mazor, M;Kawano, Y;Kypta, RM
通讯作者：
Kypta, RM
影响因子：
11.5
作者：
Miyashita, Katsuyoshi;Kawakami, Kazuyuki;Minamoto, Toshinari
通讯作者：
Minamoto, Toshinari