Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung 433, Taiwan, R.O.C.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan, R.O.C.
Oncol Rep. 2019 Mar;41(3):2060-2066. doi: 10.3892/or.2019.6958. Epub 2019 Jan 9.
Triple‑negative breast cancers (TNBCs) lack the estrogen receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Therefore, hormone or targeted therapies are not effective in the treatment of TNBC and thus the development of novel therapeutic strategies is crucial. Methotrexate (MTX), a folate antagonist, has been used in the treatment of various types of cancer; however, the anticancer effects of MTX treatment on breast cancer have thus far been ineffective. Vitamin E variants and derivatives have been applied for cancer therapy. Previous studies have indicated that vitamin E variants and derivatives exert distinct anticancer effects on different types of cancer. However, whether MTX plus vitamin E variants or its derivatives can inhibit TNBC remains unclear. The aim of the present study was to examine the anticancer effects and mechanisms of action of MTX in combination with vitamin E variants (α‑tocopherol) and derivatives (α‑tocopherol succinate) on TNBC. In the present study, MTT assay and western blot analysis were used to determine the cell survival rates and protein levels. The results demonstrated that combination treatment with MTX and α‑tocopherol suppressed TNBC cell proliferation. In addition, various concentrations of MTX exerted distinct cytotoxic effects on α‑tocopherol succinate‑treated cells. Furthermore, high‑dose MTX enhanced α‑tocopherol succinate‑induced anticancer activity; however, low‑dose MTX inhibited α‑tocopherol succinate‑induced anticancer activity. The present study also demonstrated that caspase‑3 activation and poly(adenosine diphosphate‑ribose) polymerase cleavage were observed in the α‑tocopherol succinate/MTX‑treated cells. In conclusion, the findings of the present study demonstrated that high‑dose MTX enhanced anticancer activity in α‑TOS‑treated TNBC, while low‑dose MTX reduced anticancer activity in α‑TOS‑treated TNBC.
三阴性乳腺癌（TNBC）缺乏雌激素受体、孕激素受体（PR）和人表皮生长因子受体 2（HER2）。因此，激素或靶向治疗对 TNBC 的治疗无效，因此开发新的治疗策略至关重要。甲氨蝶呤（MTX）是一种叶酸拮抗剂，已用于治疗各种类型的癌症；然而，迄今为止，MTX 治疗对乳腺癌的抗癌作用并不有效。维生素 E 变体和衍生物已应用于癌症治疗。先前的研究表明，维生素 E 变体和衍生物对不同类型的癌症具有不同的抗癌作用。然而，MTX 加维生素 E 变体或其衍生物是否能抑制 TNBC 尚不清楚。本研究旨在探讨 MTX 联合维生素 E 变体（α-生育酚）和衍生物（α-生育酚琥珀酸酯）对 TNBC 的抗癌作用及其作用机制。在本研究中，采用 MTT 检测法和 Western blot 分析检测细胞存活率和蛋白水平。结果表明，MTX 与 α-生育酚联合治疗可抑制 TNBC 细胞增殖。此外，不同浓度的 MTX 对 α-生育酚琥珀酸酯处理的细胞产生不同的细胞毒性作用。此外，高剂量 MTX 增强了 α-生育酚琥珀酸酯诱导的抗癌活性；然而，低剂量 MTX 抑制了 α-生育酚琥珀酸酯诱导的抗癌活性。本研究还表明，α-生育酚琥珀酸酯/MTX 处理的细胞中观察到 caspase-3 激活和聚（腺苷二磷酸核糖）聚合酶裂解。综上所述，本研究结果表明，高剂量 MTX 增强了 α-TOS 处理的 TNBC 的抗癌活性，而低剂量 MTX 降低了 α-TOS 处理的 TNBC 的抗癌活性。
