Department of Obstetrics and Gynecology, West China Second Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
West China Laboratory of Molecular Genetics, Sichuan University, Chengdu, China.
Singapore Med J. 2021 Feb;62(2):96-103. doi: 10.11622/smedj.2019138. Epub 2019 Nov 4.
Dihydroartemisinin (DHA) is a first-line antimalarial drug with relatively low toxicity. DHA has been speculated to possess a broad-spectrum antitumour effect. However, the potential value of DHA for the treatment of endometrial carcinoma or cervical cancer is unclear.
We used human endometrial cancer cells and cervical cancer cells to assess whether DHA alone or when combined with cisplatin would induce cell death. We aimed to elucidate the role of autophagy in DHA-induced cytotoxicity in both endometrial and cervical cancer cells, and explore the impact of DHA treatment on cell proliferation, apoptosis and autophagy.
DHA alone or in combination with cisplatin induced cell death in a dose- and time-dependent manner. Caspase-3 mRNA and cleaved caspase-3 protein levels were markedly elevated following DHA treatment either in the presence or absence of cisplatin, suggesting a role of apoptosis in DHA-induced cell death. DHA treatment activated the autophagic pathway, as evidenced by increased monodansylcadaverine-positive staining, elevated microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, and enhanced p62/sequestosome 1 degradation. Inhibition of autophagy by 3-methyladenine further enhanced the cytotoxicity of DHA towards tumour cells. mRNA levels of transferrin receptor (TfR) were suppressed upon DHA treatment and knockdown of TfR by RNA interference caused further DHA induction of cancer cell death.
Our results suggest a clinical value for DHA in the treatment of endometrial carcinoma and cervical cancer. Our data revealed possible anticancer mechanisms of DHA that involve regulating apoptosis, autophagy pathway and levels of TfR.
二氢青蒿素（DHA）是一种毒性相对较低的一线抗疟药物。DHA 被推测具有广谱抗肿瘤作用。然而，DHA 治疗子宫内膜癌或宫颈癌的潜在价值尚不清楚。
我们用人子宫内膜癌细胞和宫颈癌细胞来评估 DHA 单独或与顺铂联合使用是否会诱导细胞死亡。我们旨在阐明自噬在 DHA 诱导的子宫内膜和宫颈癌细胞细胞毒性中的作用，并探讨 DHA 治疗对细胞增殖、凋亡和自噬的影响。
DHA 单独或与顺铂联合使用以剂量和时间依赖的方式诱导细胞死亡。DHA 处理后，无论是存在顺铂还是不存在顺铂，caspase-3 mRNA 和裂解的 caspase-3 蛋白水平均明显升高，表明凋亡在 DHA 诱导的细胞死亡中起作用。DHA 处理激活了自噬途径，这表现为单丹磺酰尸胺阳性染色增加、微管相关蛋白 1 轻链 3（LC3）-II/LC3-I 比值升高以及 p62/自噬体 1 降解增强。自噬的抑制通过 3-甲基腺嘌呤进一步增强了 DHA 对肿瘤细胞的细胞毒性。DHA 处理后转铁蛋白受体（TfR）的 mRNA 水平受到抑制，并且通过 RNA 干扰敲低 TfR 导致 DHA 诱导的癌细胞死亡进一步增加。
我们的结果表明 DHA 在治疗子宫内膜癌和宫颈癌方面具有临床价值。我们的数据揭示了 DHA 的可能抗癌机制，涉及调节细胞凋亡、自噬途径和 TfR 水平。
