The sulfonamide anticancer agent indisulam enhances the chemosensitivity of gastric cancer cells by targeting FKBP8.

The application of platinum-based chemotherapy is often limited by drug resistance, which involves multiple signalling pathways. Although the sulfonamide anticancer agent indisulam has been utilised as an adjuvant in combination with cisplatin, olaparib, and temozolomide in clinical trials, the mechanism by which indisulam modulates the sensitivity of gastric cancer cells to these drugs remains elusive. Here, flow cytometry, TUNEL, and CCK-8 assays demonstrated that indisulam induced apoptosis in gastric cancer cells and enhanced their sensitivity to cisplatin and oxaliplatin. Label-free quantitative proteomics identified FKBP8 as a previously undescribed downstream target of indisulam in gastric cancer cells. qPCR analysis of clinical samples revealed a strong correlation between the mRNA levels of FKBP8 and RBM39, and Kaplan-Meier plot analyses indicated that high expression of FKBP8 mRNA was associated with reduced survival time for gastric cancer patients. Mechanistically, indisulam attenuated FKBP8 transcription, and depletion of FKBP8 enhanced apoptosis and reduced colony formation in the presence of cisplatin and oxaliplatin, thereby improving the chemotherapeutic response of gastric cancer cells to these drugs. FKBP8 overexpression abrogated the effect of indisulam and cisplatin on apoptosis and cell proliferation. Experiments using a xenograft mouse model further demonstrated that the combination of indisulam and cisplatin significantly inhibited the growth of gastric cancer cells, reduced FKBP8 mRNA levels, and increased apoptosis. Taken together, this and previous studies suggest that indisulam can inhibit viability and migration, but promote apoptosis of gastric cancer cells through distinct downstream targets, suggesting that FKBP8 could be leveraged as a therapeutic target in combination with chemotherapy for gastric cancer.