Jung Ae Ryang, Kim Ga Eun, Kim Mee Young, Rhew Seung Ah, Shin Dongho, Ha U-Syn, Hong Sung-Hoo, Lee Ji Youl, Kim Sae Woong, Park Yong Hyun
Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
Int J Mol Sci. 2025 Nov 11;26(22):10922. doi: 10.3390/ijms262210922.
Tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, are standard treatments for renal cell carcinoma (RCC). However, most patients treated with these drugs eventually develop drug resistance and relapse; therefore, new treatment options for RCC are urgently required. Recent studies have focused on combination therapies targeting distinct molecular pathways that may produce synergistic effects and help overcome drug resistance in RCC. Niclosamide, an anthelmintic agent, is effective against various cancers; however, its potential in combination with sunitinib for treating RCC has not been evaluated. In this study, we assessed the therapeutic efficacy of niclosamide in combination with sunitinib against RCC and explored the underlying molecular mechanisms. Niclosamide alone inhibited RCC cell proliferation, whereas its combination with sunitinib produced a synergistic anticancer effect, both in vitro and in vivo. RNA sequencing (RNA-seq) and bioinformatic analyses showed that niclosamide modulated critical pathways, including - and -mediated DNA repair and -regulated cell cycle progression. These findings provide proof-of-concept that niclosamide enhances TKI efficacy through modulation of DNA repair and cell cycle pathways, supporting the rationale for DNA damage response (DDR)-targeted combination strategies in RCC.
酪氨酸激酶抑制剂（TKIs），如舒尼替尼和索拉非尼，是肾细胞癌（RCC）的标准治疗药物。然而，大多数接受这些药物治疗的患者最终会产生耐药性并复发；因此，迫切需要针对RCC的新治疗方案。最近的研究集中在针对不同分子途径的联合疗法上，这些途径可能产生协同效应并有助于克服RCC中的耐药性。氯硝柳胺是一种驱虫剂，对多种癌症有效；然而，其与舒尼替尼联合治疗RCC的潜力尚未得到评估。在本研究中，我们评估了氯硝柳胺与舒尼替尼联合治疗RCC的疗效，并探讨了潜在的分子机制。单独使用氯硝柳胺可抑制RCC细胞增殖，而其与舒尼替尼联合使用在体外和体内均产生协同抗癌作用。RNA测序（RNA-seq）和生物信息学分析表明，氯硝柳胺调节关键途径，包括 - 和 - 介导的DNA修复以及 - 调节的细胞周期进程。这些发现提供了概念验证，即氯硝柳胺通过调节DNA修复和细胞周期途径增强TKI疗效，支持了RCC中以DNA损伤反应（DDR）为靶点的联合策略的理论依据。
