SKLB-23bb, AHDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules
SKLB-23bb, AHDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules
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SKLB-23bb，AHDAC6 选择性抑制剂，通过额外靶向微管表现出卓越的广谱抗肿瘤活性
DOI：
10.1158/1535-7163.mct-17-0332
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发表时间：
2018
影响因子：
5.7
通讯作者：
Chen Lijuan
中科院分区：
文献类型：
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作者：
Wang Fang;Zheng Li;Yi Yuyao;Yang Zhuang;Qiu Qiang;Wang Xiaoyan;Yan Wei;Bai Peng;Yang Jianhong;Li Dan;Pei Heying;Niu Ting;Ye Haoyu;Nie Chunlai;Hu Yiguo;Yang Shengyong;Wei Yuquan;Chen Lijuan
我们之前的研究报道了口服生物可利用的hdac6选择性抑制剂SKLB-23bb在体外抗肿瘤效果优于最近在II期临床试验中的hdac6选择性抑制剂ACY1215。本研究主要探讨SKLB-23bb活性的相关机制。我们发现，尽管具有与ACY1215相同的hdac6选择性抑制作用，但SKLB-23bb在低亚微摩尔水平上对一组实体和血液肿瘤细胞系显示细胞毒性作用。有趣的是，与报道的hdac6选择性抑制剂相比，SKLB-23bb对实体肿瘤细胞更有效。利用CRISPR-Cas9基因编辑构建的HDAC6稳定敲除细胞系，我们发现SKLB-23bb可以保持独立于HDAC6状态的细胞毒性。机制研究证实，SKLB-23bb通过额外靶向微管发挥其细胞毒活性。SKLB-23bb可以结合β-微管蛋白中的秋水仙碱位点，作为微管聚合抑制剂。与其微管破坏能力一致，SKLB-23bb还阻断肿瘤细胞G2-M期周期并引发细胞凋亡。在实体瘤异种移植物中，口服SKLB-23bb可有效抑制肿瘤生长。这些结果表明，SKLB-23bb是一种口服生物可利用的HDAC6和微管双重靶向剂。微管靶向谱增强了SKLB-23bb的抗肿瘤活性，扩大了SKLB-23bb的抗肿瘤谱，突破了HDAC6抑制剂的局限性。巨蟹座；17 (4);763 - 75。AACR©2018。
Our previous study reported that SKLB-23bb, an orally bioavailable HDAC6-selective inhibitor, exhibited superior antitumor efficiency bothin vitroandin vivoin comparison with ACY1215, a HDAC6-selective inhibitor recently in phase II clinical trial. This study focused on the mechanism related to the activity of SKLB-23bb. We discovered that despite having HDAC6-selective inhibition equal to ACY1215, SKLB-23bb showed cytotoxic effects against a panel of solid and hematologic tumor cell lines at the low submicromolar level. Interestingly, in contrast to the reported HDAC6-selective inhibitors, SKLB-23bb was more efficient against solid tumor cells. Utilizing HDAC6 stably knockout cell lines constructed by CRISPR–Cas9 gene editing, we illustrated that SKLB-23bb could remain cytotoxic independent of HDAC6 status. Investigation of the mechanism confirmed that SKLB-23bb exerted its cytotoxic activity by additionally targeting microtubules. SKLB-23bb could bind to the colchicine site in β-tubulin and act as a microtubule polymerization inhibitor. Consistent with its microtubule-disrupting ability, SKLB-23bb also blocked tumor cell cycle at G2–M phase and triggered cellular apoptosis. In solid tumor xenografts, oral administration of SKLB-23bb efficiently inhibited tumor growth. These results suggested that SKLB-23bb was an orally bioavailable HDAC6 and microtubule dual targeting agent. The microtubule targeting profile enhanced the antitumor activity and expanded the antitumor spectrum of SKLB-23bb, thus breaking through the limitation of HDAC6 inhibitors.Mol Cancer Ther; 17(4); 763–75. ©2018 AACR.