Tan Mingdian, Ye Wei, Liu Yi, Chen Xiaowu, Huttad Lakshmi, Chua Mei-Sze, So Samuel
Department of Surgery, School of Medicine, Asian Liver Center, Stanford University, Palo Alto, CA, USA.
Guangzhou JOYO Pharmaceutical Co. Ltd, Guangzhou, China.
Br J Pharmacol. 2025 Jul 22. doi: 10.1111/bph.70126.
Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, has limited treatment options and high mortality rate. We previously used a bioinformatics approach to identify niclosamide (NIC) as a promising repurposed drug candidate for HCC. However, its poor water solubility and low bioavailability limit its clinical efficacy. It's mechanisms of action are not yet fully understood.
We designed a water-soluble NIC prodrug (NIC-PS) and evaluated its efficacy (as single agent, or in combination with sorafenib or anti-PD-L1) and mechanisms using cell-based functional assays and HCC patient-derived xenograft (PDX) mouse models. We established vasorin knockout mouse tumour models and used RNA-seq to investigate the role of vasorin in mediating NIC-PS function. Western blotting and real-time PCR were used to validate the RNA-seq data and the biological effects of NIC-PS and vasorin.
NIC-PS exhibited a 10-fold increase in oral bioavailability and > 75% reduction in tumour volume in HCC PDX models. NIC binds to vasorin, and both NIC and NIC-PS suppressed vasorin expression, leading to suppression of TGFβ signalling and SMAD2/3 phosphorylation. NIC-PS enhanced the sensitivity of HCC cells and PDX to treatment with sorafenib or anti-PD-L1. Vasorin knockout results in similar effects as NIC-PS, suggesting that it partially mediates the actions of NIC-PS.
NIC-PS demonstrated improved bioavailability and antitumour efficacy compared with NIC and a potential for combination therapy with standard of care agents in HCC treatment. We also revealed its novel mechanism of action in targeting vasorin.
肝细胞癌（HCC）是全球癌症相关死亡的第三大主要原因，治疗选择有限且死亡率高。我们之前使用生物信息学方法将氯硝柳胺（NIC）鉴定为一种有前景的用于HCC的重新利用药物候选物。然而，其较差的水溶性和低生物利用度限制了其临床疗效。其作用机制尚未完全了解。
我们设计了一种水溶性NIC前药（NIC-PS），并使用基于细胞的功能测定和HCC患者来源的异种移植（PDX）小鼠模型评估其疗效（作为单一药物，或与索拉非尼或抗PD-L1联合使用）和作用机制。我们建立了血管生成素敲除小鼠肿瘤模型，并使用RNA测序来研究血管生成素在介导NIC-PS功能中的作用。蛋白质免疫印迹和实时PCR用于验证RNA测序数据以及NIC-PS和血管生成素的生物学效应。
在HCC PDX模型中，NIC-PS的口服生物利用度提高了10倍，肿瘤体积减少了>75%。NIC与血管生成素结合，NIC和NIC-PS均抑制血管生成素表达，导致TGFβ信号传导和SMAD2/3磷酸化受到抑制。NIC-PS增强了HCC细胞和PDX对索拉非尼或抗PD-L1治疗的敏感性。血管生成素敲除产生与NIC-PS类似的效果，表明它部分介导了NIC-PS的作用。
与NIC相比，NIC-PS显示出更高的生物利用度和抗肿瘤疗效，并且在HCC治疗中具有与标准治疗药物联合治疗的潜力。我们还揭示了其靶向血管生成素的新作用机制。
