Amjadi Omolbanin, Hedayatizadeh-Omran Akbar, Zaboli Ehsan, Janbabaei Ghasem, Lira Sergio A, Ahangari Ghasem
Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
Gastro-intestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
Curr Cancer Drug Targets. 2025;25(5):496-508. doi: 10.2174/0115680096303479240614061136.
Globally, Gastric Cancer (GC) ranks as the fifth leading cause of cancer-related deaths. GC is a multifaceted malignancy with diverse etiologies; however, understanding the shared molecular mechanisms can aid in discovering novel targeted therapies for GC. This study has employed a drug repositioning approach to explore new drug candidates for treating GC.
The human GC cell lines AGS, MKN-45, and KATO-III were treated with different concentrations of dopamine, cabergoline, thioridazine, and entacapone to determine effective doses and IC50 values. , cytotoxic activity on cancer cell lines was screened based on dose/time using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR) was used to measure the mRNA expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and Proliferating Cell Nuclear Antigen (PCNA) in each group. The percentage of apoptotic cells was evaluated using Annexin V/PI staining.
Dopamine, cabergoline, thioridazine, and entacapone elicited cytotoxic effects on AGS and KATO-III cells in a dose-dependent manner and elevated the percentage of Annexin Vpositive cells, suggesting the occurrence of apoptosis. The expression of Bcl-2 and PCNA was significantly decreased, whereas the expression of Bax was considerably increased in the AGS and KATO-III cells compared to that in the blank group (p < 0.05); however, no similar effect was observed in MKN-45 cells.
Through experiments, this study provides evidence that the antipsychotic drugs cabergoline, dopamine, thioridazine, and entacapone can inhibit gastric cancer growth in AGS and KATO-III cells. These findings suggest that these drugs could be repurposed as novel therapeutic agents for the treatment of gastric cancer.
在全球范围内，胃癌（GC）是癌症相关死亡的第五大主要原因。胃癌是一种具有多种病因的多方面恶性肿瘤；然而，了解其共同的分子机制有助于发现针对胃癌的新型靶向治疗方法。本研究采用药物重新定位方法来探索治疗胃癌的新候选药物。
用不同浓度的多巴胺、卡麦角林、硫利达嗪和恩他卡朋处理人胃癌细胞系AGS、MKN - 45和KATO - III，以确定有效剂量和IC50值。使用3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基四氮唑溴盐（MTT）法，基于剂量/时间筛选对癌细胞系的细胞毒性活性。采用定量逆转录聚合酶链反应（qRT - PCR）测量每组中B细胞淋巴瘤2（Bcl - 2）、Bcl - 2相关X蛋白（Bax）和增殖细胞核抗原（PCNA）的mRNA表达。使用膜联蛋白V/碘化丙啶（Annexin V/PI）染色评估凋亡细胞的百分比。
多巴胺、卡麦角林、硫利达嗪和恩他卡朋对AGS和KATO - III细胞产生剂量依赖性细胞毒性作用，并提高了膜联蛋白V阳性细胞的百分比，表明发生了凋亡。与空白组相比，AGS和KATO - III细胞中Bcl - 2和PCNA的表达显著降低，而Bax的表达显著增加（p < 0.05）；然而，在MKN - 45细胞中未观察到类似效果。
通过实验，本研究提供了证据表明抗精神病药物卡麦角林、多巴胺、硫利达嗪和恩他卡朋可抑制AGS和KATO - III细胞中的胃癌生长。这些发现表明这些药物可重新用作治疗胃癌的新型治疗剂。
