Wu Meng, Cui Jingyi, Hou Huimin, Li Ying, Liu Shengjie, Wan Li, Zhang Lili, Huang Wei, Sun Gaoyuan, Liu Jingchao, Jin Pengfei, He Shunmin, Liu Ming
Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Front Pharmacol. 2022 Apr 25;13:871259. doi: 10.3389/fphar.2022.871259. eCollection 2022.
The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2-p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC. To investigate the functions and mechanisms of XR-2 in prostate cancer, and biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities of XR-2 were evaluated by different xenografts mice models. XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both and . Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities with favourable safety. MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both and . XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.
肿瘤抑制因子p53的失活在去势抵抗性前列腺癌（CRPC）的第二代抗雄激素（SGA）耐药和神经内分泌分化中起重要作用。通过阻断MDM2-p53相互作用来重新激活p53，是野生型或具有功能的p53癌症中一种有吸引力的治疗方法。MDM2-p53抑制剂能否克服CRPC中的SGA耐药性仍需进一步研究。在此，我们研究了一种新型MDM2-p53抑制剂XR-2在CRPC中的抗肿瘤疗效及其机制。为了研究XR-2在前列腺癌中的功能和机制，我们进行了生物功能检测。采用蛋白质免疫印迹法和qRT-PCR检测相关基因的蛋白质和mRNA表达水平。通过CCK8、集落形成、流式细胞术和衰老检测等方法进行细胞功能鉴定。RNA测序和生物信息学分析主要用于确定XR-2对前列腺癌细胞转录组的影响。采用皮下接种22Rv1来源的异种移植小鼠模型研究XR-2的抗肿瘤活性。此外，通过不同的异种移植小鼠模型评估XR-2的广谱抗肿瘤活性。XR-2可直接与MDM2结合，有效重新激活p53信号通路，从而诱导野生型p53的CRPC细胞系发生细胞周期阻滞和凋亡。由于p53调节雄激素受体（AR）转录抑制且MDM2参与AR降解，XR-2还可抑制AR信号通路。因此，XR-2能有效抑制CRPC细胞活力，与恩杂鲁胺显示出协同效应，并克服了恩杂鲁胺耐药性。此外，结果表明XR-2具有广谱抗肿瘤活性且安全性良好。MDM2-p53抑制剂（XR-2）在体内和体外均具有显著的抑制前列腺癌进展的活性。XR-2与恩杂鲁胺显示出协同效应，并克服了恩杂鲁胺耐药性。
