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dc.contributor.authorFox, Jennifer Marie
dc.date.accessioned2015-07-01T14:14:48Z
dc.date.available2016-01-29T19:25:04Z
dc.date.issued2015
dc.identifier.urihttp://hdl.handle.net/10713/4616
dc.descriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2015en_US
dc.description.abstractArtemisinins are endoperoxide-containing molecules derived from the natural compound artemisinin. Although best known as antimalarials, artemisinins also have potent antineoplastic activity. The purpose of this study was to characterize the in vitro anti-leukemic activity of artesunate (AS), a monomeric artemisinin derivative in worldwide use for malaria treatment, and ART-838, a novel artemisinin dimer. Both AS and ART-838 inhibited growth of all 23 tested acute leukemia cell lines, including several harboring mutations known to confer poor prognoses in patients (MLL rearrangement and FLT3 internal tandem duplication [FLT3/ITD]). ART-838 more potently induced cell cycle arrest, caspase-dependent apoptosis, and ROS generation, than did AS. Pretreatment with the antioxidant N-Acetyl-L-cysteine (NAC) or the superoxide scavenger Tiron abrogated AS-induced growth inhibition and apoptosis, demonstrating that ROS generation is an important component of the anti-leukemic mechanism of AS. While ART-838-induced apoptosis was reduced in the presence of the NAC, antioxidant pretreatment offered little to no protection against ART-838's antiproliferative effects, suggesting additional, ROS-independent, mechanisms. Though both ART-838 and AS synergized with current chemotherapy drugs to inhibit leukemia cell growth, ART-838 synergized with FLT3 inhibitors more effectively than did AS, further suggesting mechanistic differences between the monomer and the dimer. Despite over 20 years of study, the artemisinins' full antineoplastic mechanisms of action have yet to be elucidated. A synthetic lethal drug combination screen with AS/ART-838 and a library of targeted inhibitors was used to discover novel synergistic combinations and to identify novel anti-leukemic mechanisms of action of artemisinins, as well as potential mechanisms of resistance, including activation of compensatory signaling pathways. In the screen and in subsequent validation experiments AS or ART- 838 potently synergized with the BCL2 inhibitors ABT-199 and ABT-737, potentially due to MCL1/BCL2 downregulation and/or BAX upregulation by AS/ART-838. The potent anti-leukemic efficacy of AS and especially ART-838 supports further development of the artemisinins, alone and in combinations, to treat acute leukemias.en_US
dc.language.isoen_USen_US
dc.subject.meshArtemisininsen_US
dc.subject.meshDrug Combinationsen_US
dc.subject.meshLeukemiaen_US
dc.subject.meshReactive Oxygen Speciesen_US
dc.titleRepurposing Artemisinins for the Treatment of Acute Leukemiasen_US
dc.typedissertationen_US
dc.contributor.advisorCivin, Curt I.
dc.description.urinameFull Texten_US
dc.contributor.orcid0000-0002-8651-2968
refterms.dateFOA2019-02-19T18:06:21Z


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