2. Academic Validation
  3. Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner

Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner

  • Cell Oncol (Dordr). 2023 Mar 20. doi: 10.1007/s13402-023-00789-7.
Shan Huang # 1 2,  Nai-Qi Zhang # 3,  Chun-Jie Xu # 4,  Wu-Qing Huang # 5,  Dong-Xue Li 2,  Jun Li 2,  Lin-Li Yao 2,  Kristina Sundquist 3 6,  Jan Sundquist 3 6,  Shu-Heng Jiang 2,  Xin Xing 7,  Li-Peng Hu 8,  Zhi-Gang Zhang 9,  Jianguang Ji 10,  Xue-Li Zhang 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, P.R. China.
  • 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
  • 3 Center for Primary Health Care Research, Lund University/Region Skåne, Lund, Sweden.
  • 4 Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
  • 5 School of Public Health, Fujian Medical University, Fuzhou City, P.R. China.
  • 6 Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA.
  • 7 Shanghai Fengxian District Central Hospital, No. 6600, Nanfeng Road, Shanghai, 201499, China.
  • 8 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China. lphu@shsci.org.
  • 9 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China. zzhang@shsci.org.
  • 10 Center for Primary Health Care Research, Lund University/Region Skåne, Lund, Sweden. Jianguang.ji@med.lu.se.
  • 11 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China. xlzhang@shsci.org.
  • # Contributed equally.
PMID: 36939950 DOI: 10.1007/s13402-023-00789-7
Abstract

Purpose: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal Cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole.

Methods: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an APCmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms.

Results: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect.

Conclusions: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as Adjuvant agents.

Keywords

Anti-cancer drug; Colorectal cancer; Drug combination; ER stress; Pro-apoptotic UPR.

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