Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Int J Biochem Cell Biol. 2020 May;122:105739. doi: 10.1016/j.biocel.2020.105739. Epub 2020 Mar 10.
The indulgent success of arsenic trioxide (ATO) in the induction of complete remission in acute promyelocytic leukemia (APL) patients has accommodated this agent into the therapeutic protocols. However, the intrusion of unfavorable side effects had put an unanswered question on the way of the application of this agent; whether the benefits of ATO may outweigh its drawbacks. In this study, we found that when ATO is accompanied by an activator of peroxisome proliferator-activated receptors gamma (PPARγ), even the lower concentrations could induce significant inhibitory effects on the survival of NB4 through diminishing the ability of the cells to replicate DNA in the S phase of cell cycle. We also found that through suppression of the PI3K pathway, the combination of pioglitazone and ATO provided a signal through which the induction of apoptotic cell death was enhanced probably via the elevation of reactive oxygen species (ROS). With respect to the tight connection between PI3K pathway and autophagy system and given to the inhibitory effect of pioglitazone-plus-ATO on PI3K, we found that the combination of these agents not only suppressed the expression of autophagy-related genes, but also their efficacy was augmented when autophagy was inhibited in NB4; clarifying the encouraging role of autophagy in the survival maintenance of APL cells. In conclusion, given the significant efficacy as well as the safety profile of pioglitazone in potentiating the anticancer effects of chemotherapeutic drugs, the present study suggests it as a promising agent to be used in adjuvant strategy for the treatment of APL.
三氧化二砷（ATO）在诱导急性早幼粒细胞白血病（APL）患者完全缓解方面的放纵成功，使该药物适应了治疗方案。然而，不良副作用的出现，使人们对应用该药物的方式产生了疑问；ATO 的益处是否大于其弊端。在这项研究中，我们发现当 ATO 与过氧化物酶体增殖物激活受体 γ（PPARγ）的激活剂同时存在时，即使浓度较低，也能通过降低细胞在细胞周期 S 期复制 DNA 的能力，对 NB4 细胞的存活产生显著的抑制作用。我们还发现，通过抑制 PI3K 通路，吡格列酮和 ATO 的联合使用提供了一个信号，通过这个信号，通过增加活性氧（ROS），增强了细胞凋亡的诱导。鉴于 PI3K 通路和自噬系统之间的紧密联系，以及吡格列酮加 ATO 对 PI3K 的抑制作用，我们发现这些药物的联合使用不仅抑制了自噬相关基因的表达，而且当自噬在 NB4 中被抑制时，它们的疗效增强了；阐明了自噬在 APL 细胞存活维持中的促进作用。总之，鉴于吡格列酮在增强化疗药物抗癌作用方面的显著疗效和安全性，本研究表明它是一种有前途的药物，可用于辅助治疗 APL 的策略。
