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

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

doi:10.1186/s12935-025-03712-2

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

Cancer Cell Int. 2025 Mar 6;25(1):79. doi: 10.1186/s12935-025-03712-2.

Authors

Wei-Ming Cheng^#^{1

2

3

4}, Po-Chen Li^#², Minh Tran-Binh Nguyen^#^{2

5}, Yu-Teng Lin², Yu-Tang Huang², Tai-Shan Cheng^{2

6}, Thi-Huong Nguyen^{2

7}, Thu-Ha Tran^{2

8}, Tzu-Yi Huang¹, Thu-Huyen Hoang², Sin-Yu Chen², Yu-Chieh Chu⁹, Chih-Wei Wu⁹, Ming-Fen Lee¹⁰, Yi-Shiou Chiou¹¹, Hsiao-Sheng Liu^{12

13

14}, Yi-Ren Hong^{15

16}, Peter Mu-Hsin Chang^{2

17

18}, Yu-Feng Hu^{2

19

20}, Ying-Chih Chang^{21

22}, Jin-Mei Lai²³, Chi-Ying F Huang^{24

25

26

27}

Affiliations

¹ Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
² Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
³ Department of Urology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
⁴ Division of Urology, Department of Surgery, Zhongxiao Branch, Taipei City Hospital, Taipei, 115, Taiwan.
⁵ Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
⁶ Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City, 220, Taiwan.
⁷ Institute of Biotechnology and Food Technology, Thai Nguyen University of Agriculture and Forestry, Thai Nguyen, Vietnam.
⁸ Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 112, Taiwan.
⁹ Taipei First Girls High School, Taipei, 110, Taiwan.
¹⁰ Department of Nutrition, China Medical University, Taichung, 406, Taiwan.
¹¹ Master Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
¹² Medical Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
¹³ 13 M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
¹⁴ Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan.
¹⁵ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
¹⁶ Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
¹⁷ School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
¹⁸ Department of Oncology, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
¹⁹ Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
²⁰ Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan.
²¹ Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
²² Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.
²³ Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, 242, Taiwan. jmlai@mail.fju.edu.tw.
²⁴ Program in Molecular Medicine, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. cyhuang5@nycu.edu.tw.
²⁵ Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. cyhuang5@nycu.edu.tw.
²⁶ Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cyhuang5@nycu.edu.tw.
²⁷ Chong Hin Loon Memorial Cancer and Biotherapy Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. cyhuang5@nycu.edu.tw.

^# Contributed equally.

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.

Abstract

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