Repurposing pitavastatin and atorvastatin to overcome chemoresistance of metastatic colorectal cancer under high glucose conditions

Abstract

Abstract Background Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC. Methods This study employs data mining and consensus molecular subtype (CMS) techniques to identify potential drugs for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained in low or high glucose conditions were established and were used to evaluate the cytotoxic effects of potential drugs with or without 5-FU. CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of these potential drugs. Results A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. We established the CMS4 CRC cell line SW480 (SW480-HG) cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. We showed that both pitavastatin and atorvastatin can effectively inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression. Conclusion This study highlights the biomarker-guided precision medicine strategy for drug repurposing. We showcase pitavastatin and atorvastatin with the moonlighting role for treating advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.