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2015 ; 2
(4
): e1054549
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The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia
cells to chemotherapeutic agents
#MMPMID27308510
Yu Y
; Xie Y
; Cao L
; Yang L
; Yang M
; Lotze MT
; Zeh HJ
; Kang R
; Tang D
Mol Cell Oncol
2015[Oct]; 2
(4
): e1054549
PMID27308510
show ga
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.