Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.
Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul 02447, Korea.
Int J Mol Sci. 2021 Jul 29;22(15):8147. doi: 10.3390/ijms22158147.
Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).
氨苯砜（Pyri）与其他药物联合用于治疗身体、大脑或眼睛的严重寄生虫感染，并减少 HIV 感染患者的弓形体病感染。此外，Pyri 在不同的肿瘤模型中显示出显著的抗癌潜力，但作用机制尚不清楚。因此，在这项研究中，解析了 Pyri 对人慢性髓性白血病（CML）的可能抗肿瘤作用。Pyri 抑制各种类型的肿瘤细胞的生长，并对 CML 细胞表现出显著的抑制作用。除了细胞凋亡外，Pyri 还触发了持续的自噬。自噬的靶向抑制使肿瘤细胞对 Pyri 诱导的细胞凋亡敏感。此外，Pyri 还减弱了信号转导和转录激活物 5（STAT5）及其下游靶基因 Bcl-2 的激活。因此，小干扰 RNA（siRNA）介导的 STAT5 敲低增强了 Pyri 诱导的自噬和凋亡，并促进了 Pyri 对细胞活力的抑制作用。此外，Bcl-2 的异位过表达可防止细胞发生 Pyri 介导的自噬和凋亡。总体而言，数据表明，Pyri 通过衰减 STAT5-Bcl-2 级联反应，通过同时靶向细胞凋亡和自噬两种细胞死亡机制来调节其生长抑制特性。
