Abstract

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC₅₀ values for chlorpromazine and prazosin to have a molar range of 35–65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

中文翻译：

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哌唑嗪、氯丙嗪和氟哌啶醇对肝细胞癌和永生化非肿瘤肝细胞的细胞毒作用

摘要

全球每年有超过 800,000 例肝癌病例和 700,000 例死亡。超过 80% 的肝癌病例是由肝细胞癌引起的。由于无效的治疗选择和有限的手术干预，肝细胞癌很难治疗。尽管如此，用于其他医疗状况的药物，例如抗高血压药物哌唑嗪、抗精神病药物氯丙嗪和抗精神病药物氟哌啶醇，因其潜在的抗癌作用而受到关注。因此，本研究使用这些药物来研究对肝细胞癌的毒性，同时测试对非癌性肝细胞系模型 THLE-2 的副作用。治疗后，进行 XTT 细胞活力测定、细胞凋亡测定、活性氧 (ROS) 测定、凋亡蛋白质组谱和蛋白质印迹。我们计算出氯丙嗪和哌唑嗪的 IC ₅₀值，摩尔范围为 35–65 µM。我们的主要研究结果表明，这两种治疗方法都能降低 HepG2 和 THLE-2 细胞的细胞活力并产生氧化应激（p值 < 0.05）。然而，氟哌啶醇未能证明细胞活力有任何降低，表明浓度高达 100 µM 时没有抗肿瘤作用。根据我们的发现，由于缺乏裂解的 caspase-3 表达，无法建立细胞死亡机制。氯丙嗪和哌唑嗪能够绕过漫长、昂贵且困难的癌症药物审批过程的许多方面，值得进一步研究与传统化疗药物的联合使用。