Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	20	23	2014 Dec 01	6023-33	Clin Cancer Res

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
Darinaparsin	Darinaparsin	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Darinaparsin		ZIO-101\|ZIO101\|ZIO 101\|S-Dimethylarsino-Glutathione\|DMAIII(SG)		Darinaparsin is an arsenic derivative that activates MAPK signaling and inhibits Hedgehog signaling (PMID: 25381261, 25316819), and potentially leads to tumor cell killing and inhibition of tumor growth (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