卵巢癌(OC)估计在2019年在美国杀死约14,000名妇女。目前治疗OC的化疗最初显示出治疗效果,但经常会出现耐药性。此时需要具有替代靶标的治疗。在这里,我们正在描述一种新的方法,通过增加缺氧诱导因子反义转录,使这些肿瘤对标准化疗敏感。方法:进行全基因组Bru-seq分析以完全捕获用gp130抑制剂处理的OC细胞的新生转录特征,SC144.体外和体内分析,包括缺氧的表征和选择蛋白质表达,联合标准护理化疗和抗肿瘤疗效评估SC144对OC细胞缺氧诱导的生物学活性.结果:用SC144处理的OVCAR8细胞的Bru-seq分析显示缺氧相关基因上调。此外,缺氧诱导因子反义(HIF1A-AS2)的转录被诱导,从而降低了HIF-1α的表达,同时增加了NDRG1的表达。此外,我们观察到EGFR蛋白水平下降,Met,c-Myc,细胞周期蛋白D1,MMP-2,MMP-9和TF,以及Src和P130-cas的磷酸化。在前列腺癌细胞中也证实了SC144诱导的HIF-1α和NDRG1的改变。环吡罗胺(CPX)诱导与SC144相当的细胞转录谱,表明这两种化合物之间具有相似的细胞作用机制。此外,SC144使OC细胞对奥拉帕尼致敏,卡铂和顺铂,并且显示出比CPX更好的体内功效。结论:通过抑制gp130诱导低氧应激反应代表了一种设计有效的抗癌治疗方法与OC标准治疗化疗相结合的新方法,此处报道的疗效强烈支持其临床发展。
Ovarian cancer (OC) is estimated to kill ~14,000 women in the United States in 2019. Current chemotherapies to treat OC initially show therapeutic efficacy but frequently drug resistance develops, at which point therapies with alternative targets are needed. Herein, we are describing a novel approach to sensitize these tumors to standard chemotherapies by increasing the transcription of hypoxia-inducible factor antisense. Methods: Genome-wide Bru-seq analysis was performed to fully capture the nascent transcriptional signature of OC cells treated with the gp130 inhibitor, SC144. In vitro and in vivo analysis, including characterization of hypoxia and select protein expression, combination with standard of care chemotherapy and antitumor efficacy were performed to assess the biological activity of SC144 on induction of hypoxia in OC cells. Results: Bru-seq analysis of OVCAR8 cells treated with SC144 shows upregulation of hypoxia related genes. In addition, transcription of hypoxia-inducible factor antisense (HIF1A-AS2) was induced that in turn reduced expression of HIF-1α and simultaneously increased expression of NDRG1. Furthermore, we observed decreased protein levels of EGFR, Met, c-Myc, cyclin D1, MMP-2, MMP-9 and TF, and phosphorylation of Src and P130-cas. SC144-induced alterations of HIF-1α and NDRG1 were also confirmed in prostate cancer cells. Ciclopirox olamine (CPX) induces a cellular transcriptional profile comparable to SC144, suggesting a similar cellular mechanism of action between these two compounds. In addition, SC144 sensitized OC cells to olaparib, carboplatin and cisplatin, and shows better in vivo efficacy than CPX. Conclusion: Induction of hypoxic stress responses through inhibition of gp130 represents a novel approach to design effective anticancer treatments in combination with standard-of-care chemotherapy in OC and the efficacy reported here strongly supports their clinical development.