Senior Scholars Program

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

UMMS Affiliation

School of Medicine; Senior Scholars Program

Faculty Advisor

Andrew Evens

Date

12-1-2014

Document Type

Article

Medical Subject Headings

Animals; Apoptosis; Arsenic; Arsenicals; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Glutathione; Hodgkin Disease; Humans; Intracellular Space; Lymphoma, T-Cell; Mice; Mitogen-Activated Protein Kinases; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Disciplines

Cancer Biology | Neoplasms | Therapeutics

Abstract

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.

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.

Rights and Permissions

Citation: Clin Cancer Res. 2014 Dec 1;20(23):6023-33. doi: 10.1158/1078-0432.CCR-14-1532. Epub 2014 Oct 14. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Comments

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.

PubMed ID

25316819