The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.
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.
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.
Yan
Y
Yu
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Yangchun
Y
Xie
Department of Pediatrics; Xiangya Hospital; Central South University ; Changsha, Hunan, China.
Lizhi
L
Cao
Department of Pediatrics; Xiangya Hospital; Central South University ; Changsha, Hunan, China.
Liangchun
L
Yang
Department of Pediatrics; Xiangya Hospital; Central South University ; Changsha, Hunan, China.
Minghua
M
Yang
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Michael T
MT
Lotze
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Herbert J
HJ
Zeh
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Rui
R
Kang
Center for DAMP Biology; Department of Surgery; University of Pittsburgh Cancer Institute; University of Pittsburgh ; Pittsburgh, PA, USA.
Daolin
D
Tang
AML; autophagy; erastin; ferroptosis; necroptosis