Geniposide reverses oxaliplatin resistance in colorectal cancer via suppression of PI3K/AKT pathway.

BACKGROUND: As a first-line chemotherapy agent for colorectal cancer (CRC), oxaliplatin suffers from limited efficacy due to acquired resistance. This study investigated whether geniposide can overcome oxaliplatin resistance in preclinical models and elucidated the underlying molecular mechanisms.

METHODS: We employed MTT, colony formation, flow cytometry, wound healing, and Transwell assays to evaluate viability, proliferation, apoptosis, migration, and invasion in oxaliplatin-resistant CRC cells (SW480/R, LoVo/R) treated with geniposide and/or oxaliplatin. Xenograft models bearing SW480/R or LoVo/R tumors were established to assess in vivo efficacy. Immunofluorescence analysis quantified Ki67-positive proliferating cells, while Western blot measured apoptosis markers (Bax, Bcl-2) and PI3K/AKT/mTOR pathway activity.

RESULTS: Geniposide-oxaliplatin combination therapy significantly inhibited proliferation, migration, and invasion while inducing apoptosis in resistant CRC cells beyond monotherapy effects. In vivo, geniposide restored oxaliplatin sensitivity, substantially reducing tumor growth and Ki67 proliferation index. Mechanistically, geniposide suppressed phosphorylation of AKT and mTOR in both cellular and xenograft models, with maximal inhibition observed in combination groups.

CONCLUSION: Geniposide reverses oxaliplatin resistance in CRC through PI3K/AKT pathway inhibition, demonstrating that geniposide-oxaliplatin combination therapy represents a promising therapeutic strategy for oxaliplatin-resistant CRC. .