Department of Urology, Nihon University School of Medicine, 30-1, Ooyaguchikamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
Department of Anatomy, Nihon University School of Dentistry, 1-8-13, Kanda Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
Biochem Biophys Res Commun. 2022 Oct 1;623:9-16. doi: 10.1016/j.bbrc.2022.07.042. Epub 2022 Jul 16.
Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.
雄激素和雄激素受体 (AR) 通过调节下游信号在前列腺癌进展中起核心作用。尽管去势治疗 (ADT) 是大多数前列腺癌的主要治疗方法，但它们会对 ADT 产生耐药性，从而发展为去势抵抗性前列腺癌 (CRPC)。AR 与多种转录因子形成复合物对于增强子活性和转录调节很重要，这有助于癌症的进展和对 ADT 的耐药性。我们之前证明了 OCT1 在前列腺癌中与 AR 合作，并且靶向 OCT1 的吡咯-咪唑 (PI) 聚酰胺 (PIP) 抑制细胞和去势抵抗性肿瘤生长 (Obinata D 等人。Oncogene 2016)。与大多数靶向 DNA 的治疗药物不同，PIP 可以在没有药物递送系统的情况下非共价结合 DNA。在本研究中，我们开发了一种用 DNA 烷化剂氯丁醇 (ChB) 修饰的 PIP (OCT1-PIP-ChB)。然后分析了它对前列腺癌细胞 LNCaP、22Rv1 和 PC3、胰腺癌细胞 BxPC3 和结肠癌细胞 HCT116 以及非癌细胞 MCF-10A 上皮细胞生长的影响。结果表明，与其他细胞（包括非癌细胞 MCF-10A）相比，OCT1-PIP-ChB 对 22Rv1 和 LNCaP 的 IC50 明显较低。用 OCT1-PIP-ChB 的 IC50 浓度处理 CRPC 模型 22Rv1 细胞的综合基因表达分析表明，在 OCT1-PIP-ChB 处理抑制的基因集中，涉及 DNA 双链断裂修复的基因群最为丰富。重要的是，在 22Rv1 异种移植的体内研究中，我们表明与对照组相比，OCT1-PIP-ChB 显著降低了肿瘤生长，而没有显示出明显的不良反应。因此，与 ChB 结合的 PIP 可以对前列腺癌细胞增殖和去势抵抗性肿瘤生长产生显著抑制作用，表明其作为治疗剂的潜在作用。
