PO.ET02.07 · 实验与分子治疗
AOH1996，一种癌症相关 PCNA 抑制剂，恢复尿路上皮癌的铂类敏感性：体外和体内研究
AOH1996, a cancer-associated PCNA inhibitor, restores platinum sensitivity in urothelial carcinoma: In vitro and in vivo study
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摘要 Abstract
中文摘要
尿路上皮癌（UC）常对以铂类为基础的化疗产生耐药，导致治疗疗效有限和临床结局不佳。增殖细胞核抗原（PCNA）是 DNA 复制和修复的关键调节因子，而癌症相关 PCNA（caPCNA）是一种在恶性细胞中选择性表达的结构改变形式，已成为一个有前景的治疗靶点。AOH1996 是一种同类首创的小分子抑制剂，可选择性结合 caPCNA 并破坏 PCNA 依赖的生存通路。在本研究中，我们探讨了 AOH1996 在 UC 中的抗肿瘤活性及其克服以顺铂为基础化疗耐药的能力。用 AOH1996 单独或与顺铂或吉西他滨联合处理顺铂敏感（T24、BFTC905）和顺铂耐药（T24/R）的 UC 细胞系。AOH1996 显著降低了敏感和耐药细胞的细胞活力和克隆形成存活，诱导凋亡（表现为 Annexin V 阳性比例增加以及 caspase-3 和 PARP 的切割），并引起细胞周期阻滞，细胞在 S/G2 期积累。在机制上，AOH1996 下调了 PCNA 依赖的 DNA 修复信号并增强了 DNA 损伤（表现为 gammaH2AX 表达增加）。联合指数分析表明 AOH1996 与顺铂或吉西他滨之间存在协同相互作用，尤其是在顺铂耐药的 T24/R 细胞中。在 UC 异种移植小鼠模型中，AOH1996 显著抑制肿瘤生长，并进一步增强了顺铂的抗肿瘤效果，且未引起明显的全身毒性或显著的体重下降。综上，这些发现提供了临床前证据，表明用 AOH1996 靶向 caPCNA 可发挥强大的抗肿瘤活性并恢复 UC 的化疗敏感性，支持将 caPCNA 抑制作为铂类耐药疾病患者一种有前景的治疗策略。
查看英文原文 English abstract
Urothelial carcinoma (UC) frequently develops resistance to platinum-based chemotherapy, resulting in limited treatment efficacy and dismal clinical outcomes. Proliferating cell nuclear antigen (PCNA) is a key regulator of DNA replication and repair, and cancer-associated PCNA (caPCNA), a structurally altered form selectively expressed in malignant cells, has emerged as a promising therapeutic target. AOH1996 is a first-in-class small-molecule inhibitor that selectively binds caPCNA and disrupts PCNA-dependent survival pathways. In this study, we investigated the antitumor activity of AOH1996 in UC and its ability to overcome resistance to cisplatin-based chemotherapy. Cisplatin-sensitive (T24, BFTC905) and cisplatin-resistant (T24/R) UC cell lines were treated with AOH1996 alone or in combination with cisplatin or gemcitabine. AOH1996 significantly reduced cell viability and clonogenic survival in both sensitive and resistant cells, induced apoptosis as evidenced by increased Annexin V-positive fractions and cleavage of caspase-3 and PARP, and caused cell-cycle arrest with accumulation of cells in the S/G2 phase. Mechanistically, AOH1996 downregulated PCNA-dependent DNA repair signaling and enhanced DNA damage, as shown by increased gammaH2AX expression. Combination index analysis demonstrated synergistic interactions between AOH1996 and cisplatin or gemcitabine, particularly in cisplatin-resistant T24/R cells. In a xenograft mouse model of UC, AOH1996 significantly inhibited tumor growth and further potentiated the antitumor effect of cisplatin without causing overt systemic toxicity or significant body weight loss. Together, these findings provide preclinical evidence that targeting caPCNA with AOH1996 exerts robust antitumor activity and restores chemosensitivity in UC, supporting caPCNA inhibition as a promising therapeutic strategy for patients with platinum-resistant disease.
利益披露 Disclosure
K. Kuo, None..
K. Huang, None..
C. Hsu, None.