Repurposing Sulfasalazine as a Radiosensitizer in Hypoxic Human Colorectal Cancer

Area of Science:

• Oncology
• Radiotherapy
• Cancer Biology

Background:

• Overexpression of xCT transporter in cancer cells correlates with tumor progression, metastasis, and resistance to therapies.
• Sulfasalazine (SSZ), an FDA-approved drug, exhibits anticancer properties by inhibiting xCT, thereby disrupting cellular redox homeostasis.
• Reactive oxygen species (ROS) are critical for radiotherapy (RT) efficacy, with elevated levels often linked to improved treatment outcomes.

Purpose of the Study:

• To investigate the effect of Sulfasalazine (SSZ) on the radiosensitivity of human colorectal cancer (CRC) cells.
• To determine if SSZ can enhance the efficacy of radiotherapy in CRC treatment.

Main Methods:

• Treatment of human colorectal cancer cell lines (HCT116 and DLD-1) with SSZ.
• Assessment of radiosensitivity under hypoxic conditions.
• Measurement of glutathione and thioredoxin reductase levels.
• Evaluation of ROS production, DNA damage, and ferroptosis induction.
• Validation in 3D cell culture models and DLD-1 xenografts.

Main Results:

• SSZ significantly enhances the radiosensitivity of hypoxic colorectal cancer cells.
• SSZ does not alter the intrinsic radiosensitivity of cancer cells under normoxic conditions.
• The radiosensitizing effect is associated with depletion of glutathione and thioredoxin reductase, leading to excessive ROS, increased DNA damage, and ferroptosis.

Conclusions:

• SSZ acts as a potent radiosensitizer for hypoxic colorectal cancer cells by modulating redox balance and inducing oxidative stress.
• The findings support targeting xCT as a valid radiobiological strategy in cancer therapy.
• SSZ shows clinical potential as an adjuvant therapy to improve radiotherapy outcomes in colorectal cancer patients.