Drug resistance is an un-met need in the treatment of colorectal cancer (CRC). Recently, the iron-dependent regulated cell death, ferroptosis, has been emerged as a potential therapeutic strategy for overcoming drug resistance in CRC. As natural products have been tested as promising candidates to induce ferroptosis in CRC, the anti-cancer effects of aqueous extract of Orostachys japonica (OJ) were investigated in 5-fluorouracil (5-FU)-resistance acquired SNU-C5 (SNU-C5/5-FUR) CRC cells in terms of ferroptosis. The cell viability, western blotting, and flow cytometry were used for analysis. OJ showed IC50 of 280 μg/μL in vitro. Long-term treatment of OJ (250 mg/kg) effectively induced ferroptosis with decreased GPX4, transferrin receptor, and ferroportin, and increased HMGB1 in SNU-C5/5-FUR cells-xenografted tissues. Short-term treatment of OJ (up to 250 μg/mL) did not show effective ferroptosis with slightly increased GPX4, transferrin receptor, and ferritin heavy chain. Co-treatment with ferroptosis inducers (RSL3 and sulfasalazine) or inhibitors (deferoxamine mesylate and ferrostatin-1) did not show any additive or synergistic effects on cell viability of SNU-C5/5- FUR cells. When co-treated with high dose deferoxamine mesylate, OJ further induced apoptosis as well as cell cycle arrest at G2/M phase. The results on ferroptosis in vitro and in vivo were inconsistent in SNU-C5/5-FUR cells, but ferroptosis in vivo indicating that other pathways might be a feasible candidate to induce ferroptosis or ferroptosis-augmented cell death in 5-FU resistant CRCs.
KEY WORDS: Ferroptosis; Orostachys japonica; Drug resistance; Colorectal cancer.
YOON, S. P. Orostachys japonica induces ferroptosis in 5-fluorouracil-resistantance acquired SNU-C5 colorectal cancer cells. Int. J. Morphol., 42(6):1508-1516, 2024.
