Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.

Autor: Häselbarth L; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany. lukas.haeselbarth@uk-erlangen.de.; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Erlangen, Germany. lukas.haeselbarth@uk-erlangen.de.; Interdisciplinary Centre for Clinical Research (IZKF), Erlangen, Germany. lukas.haeselbarth@uk-erlangen.de., Gamali S; Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany., Saul D; Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany., Krumbholz M; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Erlangen, Germany., Böttcher-Loschinski R; Department of Hematology and Oncology, Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany., Böttcher M; Department of Hematology and Oncology, Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany.; Health Campus Immunology, Inflammation and Infectiology (GC-I3), Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany., Zou D; Department of Hematology and Oncology, Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany., Metzler M; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Erlangen, Germany.; Interdisciplinary Centre for Clinical Research (IZKF), Erlangen, Germany., Karow A; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Erlangen, Germany.; Interdisciplinary Centre for Clinical Research (IZKF), Erlangen, Germany., Mougiakakos D; Department of Hematology and Oncology, Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany.; Health Campus Immunology, Inflammation and Infectiology (GC-I3), Medical Center, Otto-Von-Guericke University Magdeburg, Magdeburg, Germany.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2023 Nov 27; Vol. 23 (1), pp. 1153. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1186/s12885-023-11623-6
Abstrakt: Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic agent. Stress-related apoptosis was triggered via a caspase cascade including the cleavage of caspase 3 and the inactivation of poly ADP ribose polymerase 1 (PARP1). The inhibition of PARP by olaparib also increased CML death in combination with TKIs. Our findings suggest a rationale for combining TKIs with 8-Cl-Ado or olaparib for future clinical studies in CML.
(© 2023. The Author(s).)
Databáze: MEDLINE
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