Li Ya, Liu Siyang, Zhou Meng, Zhao Zihan, Song Dongfan, Guo Hongqian, Yang Rong
Department of Urology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.
Department of Urology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Pharmaceuticals (Basel). 2025 Aug 12;18(8):1185. doi: 10.3390/ph18081185.
: Bladder cancer is a common and heterogeneous malignancy of the urinary tract. Traditional chemotherapy using bivalent platinum drugs such as cisplatin(CDDP) is often limited by severe side effects and acquired resistance. To overcome these limitations, we explored a novel Pt(IV) prodrug, DNP, designed to release both cytotoxic cisplatin and the anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor naproxen(NPX). : We evaluated the cytotoxic activity of DNP using both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid models of bladder cancer cells. Transcriptomic analysis via RNA-seq identified apoptosis- and inflammation-related signaling pathways modulated by DNP. RNA-seq-based transcriptomic profiling revealed that DNP regulates signaling pathways associated with apoptosis and inflammation. The anti-inflammatory effects were evaluated using a lipopolysaccharide (LPS)-induced macrophage model, while the in vivo antitumor efficacy was assessed in an orthotopic MB49 bladder cancer model. : Compared with CDDP, DNP significantly increased intracellular platinum accumulation and exhibited superior cytotoxicity. It effectively inhibited tumor proliferation, induced apoptosis, and attenuated inflammation both in vitro and in vivo. : These findings suggest that DNP exerts dual antitumor effects through enhanced delivery of cytotoxic and anti-inflammatory agents, offering a promising strategy for bladder cancer therapy.
膀胱癌是一种常见的泌尿系统异质性恶性肿瘤。使用顺铂（CDDP）等二价铂类药物的传统化疗常常受到严重副作用和获得性耐药性的限制。为克服这些局限性，我们探索了一种新型铂（IV）前药DNP，其设计目的是释放具有细胞毒性的顺铂和抗炎性环氧合酶-2（COX-2）抑制剂萘普生（NPX）。
我们使用膀胱癌细胞的二维（2D）单层模型和三维（3D）球体模型评估了DNP的细胞毒性活性。通过RNA测序进行的转录组分析确定了受DNP调节的与凋亡和炎症相关的信号通路。基于RNA测序的转录组分析表明，DNP调节与凋亡和炎症相关的信号通路。使用脂多糖（LPS）诱导的巨噬细胞模型评估抗炎作用，同时在原位MB49膀胱癌模型中评估体内抗肿瘤疗效。
与顺铂相比，DNP显著增加细胞内铂的积累，并表现出更高的细胞毒性。它在体外和体内均有效抑制肿瘤增殖、诱导凋亡并减轻炎症。
这些发现表明，DNP通过增强细胞毒性和抗炎剂的递送发挥双重抗肿瘤作用，为膀胱癌治疗提供了一种有前景的策略。
