Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, 11873, Egypt.
Department of Clinical Pharmacy Practice, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, 11873, Egypt.
Can J Physiol Pharmacol. 2022 Sep 1;100(9):915-925. doi: 10.1139/cjpp-2021-0799. Epub 2022 Jun 9.
Histone deacetylase inhibitors (HDACIs) act as antiproliferative agents by promoting differentiation and inducing apoptosis. Valproic acid (VPA) is a HDACI that shows promising chemotherapeutic effect in a number of tumor cells. The present study aimed to investigate the inhibitory effect of VPA on the viability of mammary cancer cells and its enhancing effect with methotrexate (MTX) in vitro and in vivo. Treatment with VPA or MTX alone induced concentration-dependent cytotoxic effects in two breast cancer cell lines. Valproic acid increased significantly the cytotoxicity of MTX three times against MCF7. Valproic acid addition to MTX, however, did not produce any significant changes on MTX cytotoxicity against MDA-MB231. VPA (150 and 200 mg/kg) significantly inhibited the growth of Ehrlich ascites carcinoma (EAC) and solid Ehrlich carcinoma (SEC) tumor mouse models and improved results were achieved for tumor inhibition when VPA was combined with MTX (1 and 2 mg/kg) in vivo. The antitumor activity was not associated with a significant increase in toxicity or mice mortality rate. All these findings suggest that the combination of MTX and VPA may have clinical and (or) adjuvant therapeutic application in the treatment of mammary cancer.
组蛋白去乙酰化酶抑制剂 (HDACIs) 通过促进分化和诱导细胞凋亡来发挥抗增殖作用。丙戊酸 (VPA) 是一种 HDACI，在多种肿瘤细胞中表现出有希望的化疗效果。本研究旨在探讨 VPA 对乳腺癌细胞活力的抑制作用及其与甲氨蝶呤 (MTX) 在体外和体内的协同作用。VPA 或 MTX 单独处理在两种乳腺癌细胞系中诱导出浓度依赖性的细胞毒性作用。VPA 显著增加了 MTX 对 MCF7 的细胞毒性作用，使其增加了三倍。然而，VPA 与 MTX 联合使用对 MDA-MB231 的 MTX 细胞毒性没有产生任何显著变化。VPA（150 和 200mg/kg）显著抑制艾氏腹水癌（EAC）和实体艾氏癌（SEC）肿瘤小鼠模型的生长，并且当 VPA 与 MTX（1 和 2mg/kg）联合使用时，在体内获得了更好的肿瘤抑制效果。抗肿瘤活性与毒性或小鼠死亡率的显著增加无关。所有这些发现表明，MTX 和 VPA 的联合应用可能具有临床和（或）辅助治疗乳腺癌的应用前景。
