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Ref Type Journal Article
PMID (25316819)
Authors Ravi D, Bhalla S, Gartenhaus RB, Crombie J, Kandela I, Sharma J, Mazar A, Evens AM
Title The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 20
Issue 23
Date 2014 Dec 01
URL
Abstract Text 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.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.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.Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Darinaparsin ZIO-101|ZIO101|ZIO 101|S-Dimethylarsino-Glutathione|DMAIII(SG) Darinaparsin, is an arsenic containing compound that inhibits signaling via the MAPK and Hedgehog signaling pathways (PMID: 25381261, 25316819), potentially leading to tumor growth inhibition and tumor cell killing (PMID: 25381261, PMID: 25316819, PMID: 30080396).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Hodgkin's lymphoma not applicable Darinaparsin + U0126 Preclinical - Cell culture Actionable In a preclinical study, Darinaparsin treatment in combination with U0126 inhibited Erk1/2 phosphorylation and led to enhanced apoptosis in Hodgkin's lymphoma cells compared to Darinaparsin treatment alone in culture (PMID: 25316819). 25316819
Unknown unknown Hodgkin's lymphoma not applicable Darinaparsin Preclinical - Cell line xenograft Actionable In a preclinical study, Darinaparsin treatment induced cell cycle arrest and apoptosis, and inhibited viability of Hodgkin's lymphoma cells in culture, and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 25316819). 25316819
Unknown unknown Hodgkin's lymphoma not applicable Darinaparsin + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Darinaparsin treatment in combination with Koselugo (selumetinib) inhibited Erk1/2 phosphorylation and led to enhanced apoptosis in Hodgkin's lymphoma cells compared to Darinaparsin treatment alone in culture (PMID: 25316819). 25316819
Unknown unknown non-Hodgkin lymphoma not applicable Darinaparsin Preclinical - Cell line xenograft Actionable In a preclinical study, Darinaparsin treatment induced cell cycle arrest and apoptosis, and inhibited viability of T-cell lymphoma cells in culture, and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 25316819). 25316819