Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.
Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.
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DOI：
10.1016/j.canlet.2016.10.025
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发表时间：
2017-01-28
期刊：
影响因子：
9.7
通讯作者：
Ahmad, Nihal
中科院分区：
文献类型：
--
作者：
Cholewa, Brian D.;Ndiaye, Mary A.;Huang, Wei;Liu, Xiaoqi;Ahmad, Nihal
本研究的目的是在体内确定Polo样激酶1（Plk 1）抑制在黑色素瘤中的治疗潜力。采用Vectra技术，我们评估了Plk 1在良性痣、恶性（I-IV期）和转移性黑色素瘤中的表达谱。我们发现了一个显着的升高Plk 1免疫染色在黑色素瘤组织。此外，第二代小分子Plk 1抑制剂BI 6727导致A375和Hs 294 T黑色素瘤细胞的生长、活力和克隆形成存活率降低，以及凋亡增加。BI 6727处理还导致黑色素瘤细胞的G2/M期和S期细胞周期停滞。重要的是，BI 6727（静脉注射; 10和25 mg/kg体重）给药导致无胸腺裸鼠中A375和Hs 294 T植入异种移植物的体内肿瘤生长显著延迟和消退。这些抗黑色素瘤作用伴随着细胞增殖降低（Ki-67染色）和细胞凋亡诱导（半胱天冬酶3激活）。此外，BI 6727处理在体外和体内均引起p53和p21的显著诱导。总体而言，我们认为Plk 1抑制可能是一种有用的方法，作为单一疗法以及与其他现有的治疗方法相结合，用于黑色素瘤管理。
The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I-IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells. BI 6727 treatment also resulted in a G2/M-as well as S-phase cell cycle arrest in melanoma cells. Importantly, BI 6727 (intravenous injection; 10 and 25 mg/kg body weight) treatment resulted in significant tumor growth delay and regression in vivo in A375- and Hs 294T- implanted xenografts in athymic nude mice. These anti-melanoma effects were accompanied with a decreased cellular proliferation (Ki-67 staining) and induction of apoptosis (caspase 3 activation). In addition, BI 6727 treatment caused a marked induction of p53 and p21 in vitro as well as in vivo. Overall, we suggest that Plk1 inhibition may be a useful approach as a monotherapy as well as in combination with other existing therapeutics, for melanoma management.
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影响因子：
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