Artesunate (ARS) has been shown to be highly effective against chloroquine-resistant malaria. In vitro studies reported that ARS has anticancer effects; however, its detrimental action on cancer cells may also play a role in its toxicity toward normal cells and its potential toxicity has not been sufficiently researched. In this study, we investigated the possible cytotoxic effects using normal BRL-3A and AML12 liver cells. The results showed that ARS dose-dependently inhibited cell proliferation and arrested the G0/G1 phase cell cycle in both BRL-3A and AML12 liver cells. Western blotting demonstrated that ARS induced a significant downregulation of cyclin-dependent kinase-2 (CDK2), CDK4, cyclin D1, and cyclin E1 in various levels and then caused apoptosis when the Bcl-2/Bax ratio decreased. Conversely, the levels of intracellular reactive oxygen species (ROS) were increased. The ROS scavenger N-acetylcysteine can significantly inhibit cell cycle arrest and apoptosis induced by ARS. Thus, the data confirmed that ARS exposure impairs normal liver cell proliferation by inducing G0/G1 cell cycle arrest and apoptosis, and this detrimental action may be associated with intracellular ROS accumulation. Collectively, the possible side effects of ARS on healthy normal cells cannot be neglected when developing therapies.

青蒿琥酯（ARS）已被证明对抗氯喹疟疾非常有效。体外研究报道，ARS具有抗癌作用。然而，其对癌细胞的有害作用也可能在其对正常细胞的毒性中起作用，并且尚未充分研究其潜在毒性。在这项研究中，我们调查了正常BRL-3A和AML12肝细胞可能产生的细胞毒性作用。结果表明，ARS剂量依赖性地抑制了BRL-3A和AML12肝细胞的细胞增殖并阻止了G0 / G1期细胞周期。Western印迹表明，ARS诱导各种水平的细胞周期蛋白依赖性激酶2（CDK2），CDK4，细胞周期蛋白D1和细胞周期蛋白E1的显着下调，然后当Bcl-2 / Bax比值降低时引起细胞凋亡。反过来，细胞内活性氧（ROS）水平升高。ROS清除剂N-乙酰半胱氨酸可显着抑制ARS诱导的细胞周期停滞和凋亡。因此，数据证实，ARS暴露通过诱导G0 / G1细胞周期停滞和凋亡而损害正常肝细胞增殖，并且这种有害作用可能与细胞内ROS积累有关。总的来说，在开发疗法时，不能忽略ARS对健康正常细胞的可能副作用。