Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma

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dc.contributor University of Helsinki, Children's Hospital en
dc.contributor University of Helsinki, Faculty of Medicine en
dc.contributor University of Helsinki, HUS Children and Adolescents en
dc.contributor University of Helsinki, HUS Children and Adolescents en
dc.contributor University of Helsinki, HUS Children and Adolescents en
dc.contributor University of Helsinki, Children's Hospital en
dc.contributor.author Eloranta, Katja
dc.contributor.author Cairo, Stefano
dc.contributor.author Liljeström, Emmi
dc.contributor.author Soini, Tea
dc.contributor.author Kyrönlahti, Antti
dc.contributor.author Judde, Jean-Gabriel
dc.contributor.author Wilson, David B.
dc.contributor.author Heikinheimo, Markku
dc.contributor.author Pihlajoki, Marjut
dc.date.accessioned 2020-09-16T06:37:01Z
dc.date.available 2020-09-16T06:37:01Z
dc.date.issued 2020-07-17
dc.identifier.citation Eloranta , K , Cairo , S , Liljeström , E , Soini , T , Kyrönlahti , A , Judde , J-G , Wilson , D B , Heikinheimo , M & Pihlajoki , M 2020 , ' Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma ' , Frontiers in oncology , vol. 10 , 1138 . https://doi.org/10.3389/fonc.2020.01138 en
dc.identifier.issn 2234-943X
dc.identifier.other PURE: 144257461
dc.identifier.other PURE UUID: 28be616e-6591-4f46-aee7-15999b918f81
dc.identifier.other WOS: 000560093100001
dc.identifier.uri http://hdl.handle.net/10138/319386
dc.description.abstract Background:Hepatoblastoma (HB) is the most common pediatric liver malignancy. Despite advances in chemotherapeutic regimens and surgical techniques, the survival of patients with advanced HB remains poor, underscoring the need for new therapeutic approaches. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. We examined the antineoplastic activity of CQ in cell models of aggressive HB. Methods:Seven human HB cell models, all derived from chemoresistant tumors, were cultured as spheroids in the presence of relevant concentrations of CQ. Morphology, viability, and induction of apoptosis were assessed after 48 and 96 h of CQ treatment. Metabolomic analysis and RT-qPCR based Death Pathway Finder array were used to elucidate the molecular mechanisms underlying the CQ effect in a 2-dimensional cell culture format. Quantitative western blotting was performed to validate findings at the protein level. Results:CQ had a significant dose and time dependent effect on HB cell viability both in spheroids and in 2-dimensional cell cultures. Following CQ treatment HB spheroids exhibited increased caspase 3/7 activity indicating the induction of apoptotic cell death. Metabolomic profiling demonstrated significant decreases in the concentrations of NAD(+)and aspartate in CQ treated cells. In further investigations, oxidation of NAD(+)decreased as consequence of CQ treatment and NAD(+)/NADH balance shifted toward NADH. Aspartate supplementation rescued cells from CQ induced cell death. Additionally, downregulated expression of PARP1 and PARP2 was observed. Conclusions:CQ treatment inhibits cell survival in cell models of aggressive HB, presumably by perturbing NAD(+)levels, impairing aspartate bioavailability, and inhibiting PARP expression. CQ thus holds potential as a new agent in the management of HB. en
dc.format.extent 13
dc.language.iso eng
dc.relation.ispartof Frontiers in oncology
dc.rights en
dc.subject liver cancer en
dc.subject hepatoblastoma en
dc.subject pediatric oncology en
dc.subject poly(ADP)-ribose polymerase en
dc.subject metabolomics en
dc.subject aspartate en
dc.subject NAD(+) en
dc.subject COLORECTAL-CANCER CELLS en
dc.subject BREAST-CANCER en
dc.subject STEM-CELLS en
dc.subject IN-VITRO en
dc.subject AUTOPHAGY en
dc.subject TUMOR en
dc.subject APOPTOSIS en
dc.subject GROWTH en
dc.subject HYDROXYCHLOROQUINE en
dc.subject POLY(ADP-RIBOSE) en
dc.subject 3122 Cancers en
dc.title Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma en
dc.type Article
dc.description.version Peer reviewed
dc.identifier.doi https://doi.org/10.3389/fonc.2020.01138
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion
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