Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells

被引:37
作者
Ali, Dina [1 ,2 ]
Mohammad, Dara K. [3 ]
Mujahed, Huthayfa [1 ,2 ]
Jonson-Videsater, Kerstin [4 ]
Nore, Beston [3 ]
Paul, Christer [1 ,2 ]
Lehmann, Soren [1 ,2 ,5 ]
机构
[1] Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden
[2] Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden
[3] Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden
[4] Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden
[5] Uppsala Univ, Dept Med Sci, Uppsala, Sweden
基金
瑞典研究理事会;
关键词
APR-246 (PRIMA-1(MET)); acute myeloid leukaemia; TP53; reactive oxygen species; NFE2L2; MUTANT P53; IN-VITRO; HEMATOLOGIC MALIGNANCIES; LYMPHOCYTIC-LEUKEMIA; GENE-EXPRESSION; TP53; MUTATIONS; DNA-DAMAGE; CANCER; APOPTOSIS; CHEMOTHERAPY;
D O I
10.1111/bjh.14036
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
引用
收藏
页码:117 / 126
页数:10
相关论文
共 44 条
[1]   APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells [J].
Ali, Dina ;
Jonsson-Videsater, Kerstin ;
Deneberg, Stefan ;
Bengtzen, Sofia ;
Nahi, Hareth ;
Paul, Christer ;
Lehmann, Soren .
EUROPEAN JOURNAL OF HAEMATOLOGY, 2011, 86 (03) :206-215
[2]  
ANDERSSON BS, 1992, EXP HEMATOL, V20, P361
[3]   Regulation of p53 stability [J].
Ashcroft, M ;
Vousden, KH .
ONCOGENE, 1999, 18 (53) :7637-7643
[4]  
Breen L, 2007, ANTICANCER RES, V27, P1361
[5]   Requirement for p53 and p21 to sustain G2 arrest after DNA damage [J].
Bunz, F ;
Dutriaux, A ;
Lengauer, C ;
Waldman, T ;
Zhou, S ;
Brown, JP ;
Sedivy, JM ;
Kinzler, KW ;
Vogelstein, B .
SCIENCE, 1998, 282 (5393) :1497-1501
[6]   PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosis [J].
Bykov, VJN ;
Zache, N ;
Stridh, H ;
Westman, J ;
Bergman, J ;
Selivanova, G ;
Wiman, KG .
ONCOGENE, 2005, 24 (21) :3484-3491
[7]   Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound [J].
Bykov, VJN ;
Issaeva, N ;
Shilov, A ;
Hultcrantz, M ;
Pugacheva, E ;
Chumakov, P ;
Bergman, J ;
Wiman, KG ;
Selivanova, G .
NATURE MEDICINE, 2002, 8 (03) :282-288
[8]   4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling [J].
Chen, Huang-Hui ;
Chen, Yu-Tsen ;
Huang, Yen-Wen ;
Tsai, Hui-Ju ;
Kuo, Ching-Chuan .
FREE RADICAL BIOLOGY AND MEDICINE, 2012, 52 (06) :1054-1066
[9]   Mechanism of p53 stabilization by ATM after DNA damage [J].
Cheng, Qian ;
Chen, Jiandong .
CELL CYCLE, 2010, 9 (03) :472-478
[10]   Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase 1 gene [J].
Dhakshinamoorthy, S ;
Jaiswal, AK .
ONCOGENE, 2001, 20 (29) :3906-3917