Zhu Sha, Jiang Lili, Wang Liuyan, Wang Lingli, Zhang Cong, Ma Yu, Huang Tao
Department of Immunology, Collaborative Innovation Center of Cancer Chemoprevention, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China,
Department of Basic Medicine, School of Nursing, Zhengzhou University, Zhengzhou, Henan, China.
Cancer Manag Res. 2019 Jan 3;11:419-430. doi: 10.2147/CMAR.S179467. eCollection 2019.
Resistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success.
Xenografts from two human PCa cell lines (VCaP and CWR22) were established in male severe combined immunodeficiency mice, and MTX was administered, with or without concurrent castration, three times a week until tumors relapsed. Microarray technology was used to screen for differentially expressed genes (DEGs) in androgen-independent, MTX-resistant PCa xenografts. Gene expression profiles of MTX-treatment xenografts and their respective parental cell lines were performed using an Agilent whole human genome oligonucleotide microarray and analyzed using Ingenuity Pathway Analysis software.
A total of 636 genes were differentially expressed (fold change ≥1.5; <0.05) in MTX-resistant castration-resistant prostate cancer (CRPC) xenografts. Of these, 18 were selected to be validated and showed that most of these genes exhibited a transcriptional profile similar to that seen in the microarray (Pearson's =0.87). Western blotting conducted with a subset of genes deregulated in MTX-resistant CRPC tumors was shown through network analysis to be involved in androgen synthesis, drug efflux, ATP synthesis, and vascularization.
The present data provide insight into the genetic alterations underlying MTX resistance in androgen-independent PCa and highlight potential targets to improve therapeutic outcomes.
米托蒽醌（MTX）是一种用于晚期和转移性雄激素难治性前列腺癌（PCa）的蒽二酮类抗肿瘤药物，对其产生耐药性严重限制了治疗效果。
将两个人类PCa细胞系（VCaP和CWR22）的异种移植瘤接种到雄性严重联合免疫缺陷小鼠体内，每周三次给予MTX，同时或不同时进行去势，直至肿瘤复发。利用微阵列技术筛选雄激素非依赖性、MTX耐药性PCa异种移植瘤中差异表达的基因（DEGs）。使用安捷伦全人类基因组寡核苷酸微阵列对MTX处理的异种移植瘤及其各自的亲本细胞系进行基因表达谱分析，并使用Ingenuity Pathway Analysis软件进行分析。
在MTX耐药的去势抵抗性前列腺癌（CRPC）异种移植瘤中，共有636个基因差异表达（倍数变化≥1.5；<0.05）。其中，选择18个基因进行验证，结果显示这些基因中的大多数呈现出与微阵列中相似的转录谱（皮尔逊相关系数=0.87）。通过网络分析表明，对MTX耐药的CRPC肿瘤中一组失调基因进行蛋白质免疫印迹分析，这些基因参与雄激素合成、药物外排、ATP合成和血管生成。
本研究数据深入了解了雄激素非依赖性PCa中MTX耐药的潜在遗传改变，并突出了可能改善治疗效果的潜在靶点。
