Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor.

Abstract

PURPOSE:

The radiosensitivity of the normal intestinal epithelium is the major limiting factor for definitive radiotherapy against abdominal malignancies. Radiosensitizers, which can be used without augmenting radiation toxicity to normal tissue, are still an unmet need. Inhibition of proteosomal degradation is being developed as a major therapeutic strategy for anticancer therapy as cancer cells are more susceptible to proteasomal inhibition-induced cytotoxicity compared with normal cells. Auranofin, a gold-containing antirheumatoid drug, blocks proteosomal degradation by inhibiting deubiquitinase inhibitors. In this study, we have examined whether auranofin selectively radiosensitizes colon tumors without promoting radiation toxicity in normal intestine.

EXPERIMENTAL DESIGN:

The effect of auranofin (10 mg/kg i.p.) on the radiation response of subcutaneous CT26 colon tumors and the normal gastrointestinal epithelium was determined using a mouse model of abdominal radiation. The effect of auranofin was also examined in a paired human colonic organoid system using malignant and nonmalignant tissues from the same patient.

RESULTS:

Both in the mouse model of intestinal injury and in the human nonmalignant colon organoid culture, auranofin pretreatment prevented radiation toxicity and improved survival with the activation of p53/p21-mediated reversible cell-cycle arrest. However, in a mouse model of abdominal tumor and in human malignant colonic organoids, auranofin inhibited malignant tissue growth with inhibition of proteosomal degradation, induction of endoplasmic reticulum stress/unfolded protein response, and apoptosis.

CONCLUSIONS:

Our data suggest that auranofin is a potential candidate to be considered as a combination therapy with radiation to improve therapeutic efficacy against abdominal malignancies.

• Authors: Dhrubajyoti Nag, Payel Bhanja, Randal Riha, Giselle Sanchez-Guerrero, Bruce F Kimler, Terance T Tsue, Chris Lominska, Subhrajit Saha
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 15 Pg. 4791-4807 (08 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30940656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antirheumatic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Protective Agents
• Radiation-Sensitizing Agents
• TP53 protein, human
• Tumor Suppressor Protein p53
• Auranofin

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Apoptosis
• Auranofin (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (metabolism, pathology, radiotherapy)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Intestinal Mucosa (drug effects, injuries, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Protective Agents (pharmacology)
• Radiation Injuries (pathology, prevention & control)
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Unfolded Protein Response (drug effects)
• Xenograft Model Antitumor Assays