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dc.contributor.advisorAndrew Evens
dc.contributor.authorRavi, Dashnamoorthy
dc.contributor.authorBhalla, Savita
dc.contributor.authorGartenhaus, Ronald B.
dc.contributor.authorCrombie, Jennifer
dc.contributor.authorKandela, Irawati
dc.contributor.authorSharma, Jaya
dc.contributor.authorMazar, Andrew
dc.contributor.authorEvens, Andrew M.
dc.date2022-08-11T08:10:55.000
dc.date.accessioned2022-08-23T17:24:47Z
dc.date.available2022-08-23T17:24:47Z
dc.date.issued2014-12-01
dc.date.submitted2016-03-28
dc.identifier.citationClin Cancer Res. 2014 Dec 1;20(23):6023-33. doi: 10.1158/1078-0432.CCR-14-1532. Epub 2014 Oct 14. <a href="http://dx.doi.org/10.1158/1078-0432.CCR-14-1532">Link to article on publisher's site</a>
dc.identifier.issn1078-0432 (Linking)
dc.identifier.doi10.1158/1078-0432.CCR-14-1532
dc.identifier.pmid25316819
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49265
dc.description<p>Jennifer Crombie participated in this study as a medical student as part of the Senior Scholars research program at the University of Massachusetts Medical School.</p>
dc.description.abstractPURPOSE: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action. EXPERIMENTAL DESIGN: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V-based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK. RESULTS: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death. CONCLUSIONS: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25316819&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281835/
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectArsenic
dc.subjectArsenicals
dc.subjectCell Cycle
dc.subjectCell Death
dc.subjectCell Line, Tumor
dc.subjectCell Survival
dc.subjectDisease Models, Animal
dc.subjectExtracellular Signal-Regulated MAP Kinases
dc.subjectGlutathione
dc.subjectHodgkin Disease
dc.subjectHumans
dc.subjectIntracellular Space
dc.subjectLymphoma, T-Cell
dc.subjectMice
dc.subjectMitogen-Activated Protein Kinases
dc.subjectProtein Tyrosine Phosphatase, Non-Receptor Type 6
dc.subjectSignal Transduction
dc.subjectTumor Burden
dc.subjectXenograft Model Antitumor Assays
dc.subjectCancer Biology
dc.subjectNeoplasms
dc.subjectTherapeutics
dc.titleThe novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models
dc.typeJournal Article
dc.source.journaltitleClinical cancer research : an official journal of the American Association for Cancer Research
dc.source.volume20
dc.source.issue23
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/ssp/209
dc.identifier.contextkey8390980
html.description.abstract<p>PURPOSE: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action.</p> <p>EXPERIMENTAL DESIGN: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V-based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK.</p> <p>RESULTS: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death.</p> <p>CONCLUSIONS: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms.</p>
dc.identifier.submissionpathssp/209
dc.contributor.departmentSenior Scholars Program
dc.contributor.departmentSchool of Medicine
dc.source.pages6023-33


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