Department of Oncology, Tianjin Nankai Hospital, Tianjin, 300100, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, 300100, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, 300100, China.
Eur J Pharmacol. 2022 Jul 5;926:175028. doi: 10.1016/j.ejphar.2022.175028. Epub 2022 May 13.
Dihydroartemisinin (DHA) exhibits a direct antitumor effect in various tumor models. However, the mechanism of DHA inducing ferroptosis and activating antitumor immunity remains obscure. Therefore, our study was dedicated to investigate the effect of DHA on ferroptosis and tumor microenvironment and elucidate the underlying molecular mechanism. PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cell in vivo, including M2-type macrophages (M2), myeloid-derived suppressor cells (MDSCs), CD4T cells, CD8T cells, NK cells and NKT cells. Levels of GPX4, SLC7A11, P53 and ALOX12 were determined by Real-time PCR and Western blot. CCK8 assay was performed to detect cell viability, and the ferroptosis was distinguished by flow cytometry. Our results showed that DHA inhibited pancreatic cancer cell proliferation. In addition, DHA induced cell ferroptosis by up-regulating the expression of P53 and ALOX12, which was blocked by baicalein (a selective ALOX12 inhibitor). However, DHA also up-regulated the expression of GPX4 and SLC7A11. On the other hand, DHA significantly decreased the suppressive expansion of M2 and MDSCs. Moreover, DHA increased the immune cell population of CD8T cells, NK cells and NKT cells in the tumor tissues of the tumor-bearing mice. Whereas, the DHA treatment did not affect the frequencies of M2, MDSCs, CD4T, CD8T, NK and NKT cells in the spleen. Our research provided experimental evidences on the activity and mechanism of ferroptosis induced by DHA and revealed that DHA regulated tumor local immunosuppressive microenvironment.
双氢青蒿素（DHA）在各种肿瘤模型中表现出直接的抗肿瘤作用。然而，DHA 诱导铁死亡和激活抗肿瘤免疫的机制仍不清楚。因此，我们的研究旨在探讨 DHA 对铁死亡和肿瘤微环境的影响，并阐明其潜在的分子机制。使用 PDAC 原位肿瘤模型研究体内肿瘤增殖和免疫细胞群体，包括 M2 型巨噬细胞（M2）、髓源性抑制细胞（MDSC）、CD4T 细胞、CD8T 细胞、NK 细胞和 NKT 细胞。通过实时 PCR 和 Western blot 测定 GPX4、SLC7A11、P53 和 ALOX12 的水平。通过 CCK8 测定法检测细胞活力，并通过流式细胞术区分铁死亡。我们的结果表明 DHA 抑制胰腺癌细胞增殖。此外，DHA 通过上调 P53 和 ALOX12 的表达诱导细胞铁死亡，这被白杨素（一种选择性 ALOX12 抑制剂）阻断。然而，DHA 也上调了 GPX4 和 SLC7A11 的表达。另一方面，DHA 显著降低了 M2 和 MDSC 的抑制性扩张。此外，DHA 增加了荷瘤小鼠肿瘤组织中 CD8T 细胞、NK 细胞和 NKT 细胞的免疫细胞群体。然而，DHA 处理对脾脏中 M2、MDSC、CD4T、CD8T、NK 和 NKT 细胞的频率没有影响。我们的研究为 DHA 诱导的铁死亡的活性和机制提供了实验证据，并揭示了 DHA 调节肿瘤局部免疫抑制微环境。
