Chen Liyun, Guo Pei, Zhang Yunxiang, Li Xiaoyang, Jia Peimin, Tong Jianhua, Li Junmin
Department of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197 Rui Jin Er Road, Shanghai 200025, China; Department of Hematology, No.1 Hospital Affiliated to Suzhou University, No. 188 Shi Zi Street, Suzhou 215006, China.
Department of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197 Rui Jin Er Road, Shanghai 200025, China; Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197 Rui Jin Er Road, Shanghai 200025, China.
Leuk Res. 2017 Sep;60:44-52. doi: 10.1016/j.leukres.2017.06.007. Epub 2017 Jun 16.
Cytarabine (Ara-c) has been an important agent in acute myeloid leukemia (AML) treatment for more than 40 years. While, the mechanisms underlying low dose cytarabine (LD Ara-c) is poorly understood. In this study, we investigated the therapeutic effect of LD Ara-C in vitro. U937 and HEL cell lines were treated with increasing dose of Ara-C and showed growth inhibition rates in a time and dose-dependent manner. Treatment with LD Ara-C (50nM) induced a time-dependent increase in expression of microtubule-associated protein light chain 3 (LC3) and beclin1, but degradation of sequestosome1 (p62) in both U937 and HEL cells. Characteristic of autophagosomes appeared after 24h treatment. Meanwhile, deregulation of Akt-mTOR pathway was also detected. When cultured in presence of autophagy inhibitors, autophagy and differentiation was reversed, and cell growth inhibition was also attenuated. Similar phenomenon could also be seen when beclin1 expression was down-regulated. Taken together, we concluded that LD Ara-C can induce autophagy in AML cells and appeared to play an important role in differentiation and death. Down-regulation of Akt-mTOR pathway is involved in these processes. We suggest that cytarabine-induced autophagy is not a pro-survival mechanism, but accounts for its antineoplastic effects.
40多年来，阿糖胞苷（Ara-c）一直是急性髓系白血病（AML）治疗中的重要药物。然而，低剂量阿糖胞苷（LD Ara-c）的作用机制尚不清楚。在本研究中，我们在体外研究了LD Ara-C的治疗效果。用递增剂量的Ara-C处理U937和HEL细胞系，细胞生长抑制率呈时间和剂量依赖性。用LD Ara-C（50nM）处理可诱导U937和HEL细胞中微管相关蛋白轻链3（LC3）和贝林1（beclin1）的表达随时间增加，但隔离小体1（p62）降解。处理24小时后出现自噬体特征。同时，还检测到Akt-mTOR通路失调。当在自噬抑制剂存在下培养时，自噬和分化被逆转，细胞生长抑制也减弱。当beclin1表达下调时也可观察到类似现象。综上所述，我们得出结论，LD Ara-C可诱导AML细胞自噬，并在分化和死亡中起重要作用。Akt-mTOR通路的下调参与了这些过程。我们认为阿糖胞苷诱导的自噬不是一种促生存机制，而是其抗肿瘤作用的原因。
