Hoelzen Emma J, Radomska Hanna S, Kulp Samuel K, Adeluola Adeoluwa A, Granchie Lauren A, Cheng Jeffrey, Dauki Anees M, Campbell Moray J, Mohammed Shabber, Xing Enming, Hai Min, Fukuda Mayu, Cheng Xiaolin, Phelps Mitch A, Li Pui-Kai, Coss Christopher C
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Cancers (Basel). 2025 Jul 31;17(15):2535. doi: 10.3390/cancers17152535.
BACKGROUND/OBJECTIVES: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide's known anti-AR activity and additional anti-cancer pathway efficacy.
Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC.
Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC.
Valine-niclosamide improves upon niclosamide's poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine-niclosamide in advanced HCC and in other cancers or diseases is warranted.
背景/目的：肝细胞癌（HCC）是肝癌的主要形式，目前是全球癌症相关死亡的第二大原因。目前晚期HCC的一线全身治疗仅使患者的总生存期略有改善。HCC是一种性别差异疾病，癌症进展部分由雄激素受体（AR）活性驱动。在此，基于氯硝柳胺已知的抗AR活性和额外的抗癌途径疗效，我们提出了用于晚期HCC的新型氯硝柳胺前药。
在两种具有不同AR表型的HCC细胞系中评估氯硝柳胺类似物对AR蛋白的影响。开发了氯硝柳胺的氨基酸缀合物，并进行了药代动力学（PK）分析以确定清除率和口服暴露量的改善情况。最后，在HCC体内模型中评估氯硝柳胺类似物和氨基酸缀合物。
氯硝柳胺类似物在HCC中保持抗AR特性。缬氨酸缀合的氯硝柳胺显示出口服暴露量增加，使其成为晚期HCC的潜在治疗药物。
缬氨酸-氯硝柳胺改善了氯硝柳胺的低溶解度和口服生物利用度，增加了其在多种治疗用途中的效用。有必要对缬氨酸-氯硝柳胺在晚期HCC以及其他癌症或疾病中的作用进行进一步研究。
