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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
Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden..
Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden..
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2016 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 1, 117-126 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 174, no 1, 117-126 p.
Keyword [en]
APR-246 (PRIMA-1(MET)), acute myeloid leukaemia, TP53, reactive oxygen species, NFE2L2
National Category
Cancer and Oncology Hematology
Identifiers
URN: urn:nbn:se:uu:diva-308267DOI: 10.1111/bjh.14036ISI: 000383772300010PubMedID: 26991755OAI: oai:DiVA.org:uu-308267DiVA: diva2:1049291
Funder
Swedish Cancer SocietySwedish Research CouncilStockholm County Council
Available from: 2016-11-24 Created: 2016-11-24 Last updated: 2016-11-24Bibliographically approved

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