Repurposing pitavastatin and atorvastatin to overcome chemoresistance of metastatic colorectal cancer under high glucose conditions
Scientific Updates June 12,2025
Wei-Ming Cheng, Po-Chen Li, Minh Tran-Binh Nguyen, Yu-Teng Lin, Yu-Tang Huang, Tai-Shan Cheng, Thi-Huong Nguyen, Thu-Ha Tran, Tzu-Yi Huang, Thu-Huyen Hoang, Sin-Yu Chen, Yu-Chieh Chu, Chih-Wei Wu, Ming-Fen Lee, Yi-Shiou Chiou, Hsiao-Sheng Liu, Yi-Ren Hong, Peter Mu-Hsin Chang, Yu-Feng Hu, Ying-Chih Chang, Jin-Mei Lai, Chi-Ying F Huang

Cancer Cell Int. 2025 Mar 6;25(1):79. 

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 pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin.

Results: A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could 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. Pitavastatin and atorvastatin could be used to assist in the treatment of 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.

Keywords: Atorvastatin; Colorectal cancer; Consensus molecular subtype; Drug resistance; Hyperglycemia; Pitavastatin.


AcroCyte's Linkedin Post

We are thrilled 🎉to see AcroCyte's R3CE® technology contributing to the latest research published by Prof. Chi-Ying F. Huang's team.

Cheng, WM., Li, PC., Nguyen, M.TB. et al. Repurposing pitavastatin and atorvastatin to overcome chemoresistance of metastatic colorectal cancer under high glucose conditions. Cancer Cell Int 25, 79 (2025). https://lnkd.in/gqDpDj_K

Key Research Findings 🔬: This study demonstrates that pitavastatin and atorvastatin have the potential to overcome chemoresistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (CRC) cells under hyperglycemic conditions. These two statin drugs can inhibit cancer cell proliferation and 3D spheroid formation, synergistically enhance the cytotoxic effects of 5-FU, and induce apoptosis.

Role of the R3CE®💡: In this study, AcroCyte's R3CE 3D culture plate (a scaffold-free system) was utilized to culture DLD-1R cells, which are intrinsically resistant to 5-FU, into 3D spheroids. This allowed the researchers to observe in a more physiologically relevant 3D structure that pitavastatin and atorvastatin were more effective than 5-FU alone in reducing the volume and viability of these chemoresistant spheroids. Furthermore, these two statins could effectively downregulate the expression of the cancer stem-like cell marker CD44.

This study highlights the value of 3D cell culture systems like the AcroCyte's R3CE in cancer research🌟, as they can more accurately simulate the tumor microenvironment, thereby providing deeper insights into drug responses and facilitating the development of new strategies to overcome chemoresistance🚀.

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