Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor.

Abstract

BACKGROUND:

Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method.

METHODS:

Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU.AT/RT-6) and established AT/RT cell lines (BT-12 and BT-16) were used to assess therapeutic effects of combining DSF with radiation treatment (RT). Survival fraction by clonogenic assay, protein expression, immunofluorescence, and autophagy analysis were evaluated in vitro. Antitumor effects of combining DSF with RT were verified by bioluminescence imaging, tumor volume, and survival analysis in vivo.

RESULTS:

The results demonstrated that DSF at low concentration enhanced the radiosensitivity of AT/RT cells with reduction of survival fraction to 1.21‒1.58. DSF increased DNA double-strand break (γ-H2AX, p-DNA-PKcs, and p-ATM), apoptosis (cleaved caspase-3), autophagy (LC3B), and cell cycle arrest (p21) in irradiated AT/RT cells, while it decreased anti-apoptosis (nuclear factor-kappaB, Survivin, and B-cell lymphoma 2 [Bcl2]). In vivo, DSF and RT combined treatment significantly reduced tumor volumes and prolonged the survival of AT/RT mouse models compared with single treatments. The combined treatment also increased γ-H2AX, cleaved caspase-3, and LC3B expression and decreased ALDH1, Survivin, and Bcl2 expression in vivo.

CONCLUSIONS:

DSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment.

• Authors: Young Eun Lee, Seung Ah Choi, Pil Ae Kwack, Hak Jae Kim, Il Han Kim, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Sung-Hye Park, Kyung Duk Park, Do Won Hwang, Kyeung Min Joo, Seung-Ki Kim
• Journal: Neuro-oncology (Neuro Oncol) Vol. 19 Issue 8 Pg. 1079-1087 (Aug 01 2017) ISSN: 1523-5866 [Electronic] England
• PMID: 28340172 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]

Chemical References

• Radiation-Sensitizing Agents
• Disulfiram

Topics

• Animals
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Disulfiram (pharmacology)
• Humans
• Infant
• Male
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)
• Rhabdoid Tumor (drug therapy, metabolism)
• Teratoma (drug therapy)
• Xenograft Model Antitumor Assays (methods)