The Protozoan Inhibitor Atovaquone Affects Mitochondrial Respiration and Shows In Vitro Efficacy Against Glucocorticoid-Resistant Cells in Childhood B-Cell Acute Lymphoblastic Leukaemia.

Sbirkov, Yordan, Ivanova, Tsvetomira, Burnusuzov, Hasan, Gercheva, Kalina, Petrie, Kevin, Schenk, Tino and Sarafian, Victoria (2021) The Protozoan Inhibitor Atovaquone Affects Mitochondrial Respiration and Shows In Vitro Efficacy Against Glucocorticoid-Resistant Cells in Childhood B-Cell Acute Lymphoblastic Leukaemia. Frontiers in oncology, 11. p. 632181. ISSN 2234-943X

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Abstract

Childhood acute lymphoblastic leukaemia (cALL) accounts for about one third of all paediatric malignancies making it the most common cancer in children. Alterations in tumour cell metabolism were first described nearly a century ago and have been acknowledged as one of the key characteristics of cancers including cALL. Two of the backbone chemotherapeutic agents in the treatment of this disease, Glucocorticoids and L-asparaginase, are exerting their anti-leukaemic effects through targeting cell metabolism. Even though risk stratification and treatment regimens have improved cure rates to nearly 90%, prognosis for relapsed children remains poor. Therefore, new therapeutic approaches are urgently required. Atovaquone is a well-tolerated drug used in the clinic mainly against malaria. Being a ubiquinone analogue, this drug inhibits co-enzyme Q10 of the electron transport chain (ETC) affecting oxidative phosphorylation and cell metabolism. In this study we tested the effect of Atovaquone on cALL cells . Pharmacologically relevant concentrations of the inhibitor could effectively target mitochondrial respiration in both cALL cell lines (REH and Sup-B15) and primary patient samples. We found that Atovaquone leads to a marked decrease in basal respiration and ATP levels, as well as reduced proliferation, cell cycle arrest, and induction of apoptosis. Importantly, we observed an enhanced anti-leukaemic effect when Atovaquone was combined with the standard chemotherapeutic Idarubicin, or with Prednisolone in an model of Glucocorticoid resistance. Repurposing of this clinically approved inhibitor renders further investigations, but also presents opportunities for fast-track trials as a single agent or in combination with standard chemotherapeutics. [Abstract copyright: Copyright © 2021 Sbirkov, Ivanova, Burnusuzov, Gercheva, Petrie, Schenk and Sarafian.]

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router ** History: received 22-11-2020; accepted 02-02-2021.
Uncontrolled Keywords: acute B-cell lymphoblastic leukaemia, atovaquone, glucocorticoid resistance, metabolism, mitochondria
Divisions: Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences
SWORD Depositor: Publication Router
Depositing User: Publication Router
Date Deposited: 26 Apr 2021 16:16
Last Modified: 27 Apr 2021 13:00
URI: http://sure.sunderland.ac.uk/id/eprint/13368
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

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