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

Area of Science:

• Oncology
• Radiotherapy
• Drug Development

Background:

• Radiosensitivity of normal intestinal epithelium limits abdominal radiotherapy efficacy.
• Novel radiosensitizers are needed to improve treatment without increasing normal tissue toxicity.
• Proteasomal degradation inhibition is a promising anticancer strategy due to cancer cell susceptibility.

Purpose of the Study:

• To investigate auranofin's potential to selectively radiosensitize colon tumors.
• To determine if auranofin can mitigate radiation-induced toxicity in normal intestinal tissue.
• To explore auranofin's mechanism in both normal and malignant colon cells.

Main Methods:

• Auranofin (10 mg/kg i.p.) was tested in a mouse model of abdominal radiation, assessing effects on CT26 colon tumors and normal gastrointestinal epithelium.
• A paired human colonic organoid system, using matched malignant and nonmalignant tissues, was employed to evaluate auranofin's effects.
• Mechanisms investigated included proteasomal degradation, cell-cycle arrest, endoplasmic reticulum stress, and apoptosis.

Main Results:

• Auranofin pretreatment protected normal intestinal cells and improved survival in mouse models and human organoids via p53/p21-mediated cell-cycle arrest.
• In malignant colon tumors and organoids, auranofin inhibited growth by blocking proteasomal degradation, inducing endoplasmic reticulum stress, and promoting apoptosis.
• Selective radiosensitization of tumors without augmenting normal tissue toxicity was observed.

Conclusions:

• Auranofin demonstrates selective radiosensitization of colon tumors.
• The drug effectively reduces radiation toxicity in normal intestinal tissues.
• Auranofin is a potential candidate for combination therapy to enhance efficacy against abdominal malignancies.