Yu Yan, Xie Yangchun, Cao Lizhi, Yang Liangchun, Yang Minghua, Lotze Michael T, Zeh Herbert J, Kang Rui, Tang Daolin
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh; Pittsburgh, PA, USA; Department of Pediatrics; Xiangya Hospital; Central South University; Changsha, Hunan, China.
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Mol Cell Oncol. 2015 May 26;2(4):e1054549. doi: 10.1080/23723556.2015.1054549. eCollection 2015 Oct-Dec.
Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.
急性髓系白血病（AML）是成人中最常见的白血病类型。对化疗药物产生耐药性是AML患者有效治疗的主要障碍。喹唑啉酮衍生物艾拉斯汀最初是在筛选与RAS癌基因表达具有合成致死性的小分子时被鉴定出来的。随后发现这种致死性是通过诱导一种称为铁死亡的新型细胞死亡形式而发生的。在本研究中，我们证明艾拉斯汀以不依赖RAS的方式增强AML细胞对化疗药物的敏感性。艾拉斯汀在HL-60细胞（AML，NRAS_Q61L）中剂量依赖性地诱导与铁死亡、凋亡、坏死性凋亡和自噬相关的混合类型细胞死亡，但在Jurkat细胞（急性T细胞白血病，RAS野生型）、THP-1细胞（AML，NRAS_G12D）、K562细胞（慢性粒细胞白血病，RAS野生型）或NB-4细胞（急性早幼粒细胞白血病M3，KRAS_A18D）中未观察到。用铁死亡抑制剂Ferrostatin-1或坏死性凋亡抑制剂Necrostatin-1处理，但不用泛半胱天冬酶抑制剂Z-VAD-FMK或自噬抑制剂氯喹处理，可预防艾拉斯汀诱导的HL-60细胞生长抑制。此外，抑制c-JUN N端激酶和p38，但不抑制细胞外信号调节激酶激活，可诱导HL-60细胞对艾拉斯汀产生耐药性。重要的是，低剂量艾拉斯汀显著增强了两种一线化疗药物（阿糖胞苷/ara-C和多柔比星/阿霉素）对HL-60细胞的抗癌活性。总的来说，铁死亡和坏死性凋亡的诱导有助于艾拉斯汀诱导的生长抑制并克服AML细胞中的耐药性。
