INDOLE-3-CARBOXYLIC ACID ENHANCED ANTI-CANCER POTENCY OF DOXORUBICIN VIA INDUCTION OF CELLULAR SENESCENCE IN COLORECTAL CELLS

Colorectal cancer (CRC) is the most common gastrointestinal malignancy. Doxorubicin (DOX) is a widely utilized chemotherapy drug, but its efficacy is limited due to dose -dependent toxicity. Here, we aim to explore the effect of indole-3-carboxylic acid on DOX-induced senescence of CRC. Healthy adult rats and aged rats were compared in terms of their metabolites and functions through non -targeted metabolomics. LS180 cells were treated with DOX to induce senescence, followed by indole-3-carboxylic acid. The effects of this combination were evaluated in xenograft tumor mice. Cell viability, proliferation, and cell cycle were assessed with the Cell Counting Kit -8, colony formation assays, and flow cytometry. The levels of senescence -associated heterochromatin foci (SAHF) were detected by immunofluorescence. Senescence-associated-beta-galactosidase (SA-beta-gal) expression was assessed by SA-beta-gal staining and immunohistochemistry. Western blot was used to detect the expression of p21 and p53. Compared with healthy adult rats, the serum metabolome in aging rats was altered and the abundance of indole metabolites, including indoxyl sulfate, indole-3-carboxylic acid, and indole-5-carboxylic acid, was decreased significantly. In LS180 cells, indole-3-carboxylic acid amplified DOX-induced cell senescence, inhibiting cell proliferation and promoting cell cycle arrest. It also boosted DOX-triggered upregulation of SA-beta-gal, SAHF, and p21. In nude mice, indole-3-carboxylic acid increased the inhibitory effect of DOX on xenograft tumors. Indole-3-carboxylic acid enhanced the cellular senescence and growth arrest induced by DOX, suppressing mouse tumor growth. These findings suggest that a combined treatment of indole-3-carboxylic acid and DOX could be an effective strategy for CRC treatment.