ROS 通过调控 PTEN/PI3K/AKT 信号通路在 ATPR 诱导白血病细胞分化和抑制增殖中发挥重要作用。

ROS play an important role in ATPR inducing differentiation and inhibiting proliferation of leukemia cells by regulating the PTEN/PI3K/AKT signaling pathway.

机构信息

Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, 230032, Anhui, China.

The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.

出版信息

Biol Res. 2019 May 3;52(1):26. doi: 10.1186/s40659-019-0232-9.

BACKGROUND

Acute myeloid leukemia (AML) is an aggressive and mostly incurable hematological malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcomes. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show biological anti-tumor characteristics in our previous studies. However, its potential effect on leukemia remains unknown. The present research aims to investigate the underlying mechanism of treating leukemia with ATPR in vitro.

METHODS

In this study, the AML cell lines NB4 and THP-1 were treated with ATPR. Cell proliferation was analyzed by the CCK-8 assay. Flow cytometry was used to measure the cell cycle distribution and cell differentiation. The expression levels of cell cycle and differentiation-related proteins were detected by western blotting and immunofluorescence staining. The NBT reduction assay was used to detect cell differentiation.

RESULTS

ATPR inhibited cell proliferation, induced cell differentiation and arrested the cell cycle at the G0/G1 phase. Moreover, ATPR treatment induced a time-dependent release of reactive oxygen species (ROS). Additionally, the PTEN/PI3K/Akt pathway was downregulated 24 h after ATPR treatment, which might account for the anti-AML effects of ATPR that result from the ROS-mediated regulation of the PTEN/PI3K/AKT signaling pathway.

CONCLUSIONS

Our observations could help to develop new drugs targeting the ROS/PTEN/PI3K/Akt pathway for the treatment of AML.

背景

急性髓细胞白血病（AML）是一种侵袭性的、多数情况下无法治愈的血液系统恶性肿瘤，在对标准化疗有初步反应后经常复发。因此，迫切需要新的治疗方法来改善 AML 的临床结果。我们团队设计并合成的新型全反式视黄酸（ATRA）衍生物 4-氨基-2-三氟甲基-苯基视黄酯（ATPR）在我们之前的研究中已被证明具有生物抗肿瘤特性。然而，其对白血病的潜在作用尚不清楚。本研究旨在探讨 ATPR 体外治疗白血病的潜在机制。

方法

在这项研究中，用 ATPR 处理 AML 细胞系 NB4 和 THP-1。通过 CCK-8 测定分析细胞增殖。通过流式细胞术检测细胞周期分布和细胞分化。通过 Western blot 和免疫荧光染色检测细胞周期和分化相关蛋白的表达水平。使用 NBT 还原测定检测细胞分化。

结果

ATPR 抑制细胞增殖，诱导细胞分化，并将细胞周期阻滞在 G0/G1 期。此外，ATPR 处理诱导活性氧（ROS）的时间依赖性释放。此外，在 ATPR 处理 24 小时后，PTEN/PI3K/Akt 通路被下调，这可能是由于 ROS 介导的 PTEN/PI3K/AKT 信号通路调节导致 ATPR 具有抗 AML 作用。