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Calpain-2 Inhibitor Therapy Reduces Murine Colitis and Colitis-associated Cancer
Aaron H Rose1, Zhi Huang, Chrisy Mafnas
1*Department of Cellular and Molecular Biology, John A. Burns School of Medicine, Honolulu, Hawaii; †Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China; and ‡Department of Pathology, John A. Burns School of Medicine, Honolulu, Hawaii.
Background:
An important role has emerged for calpain enzymes in regulating inflammation with one isoform, calpain-2, particularly important for macrophage activation. The goal of this study was to determine the therapeutic potential of a synthetic calpain-2 inhibitor, zLLY-CH2F, for colitis and inflammation-associated colorectal cancer.
Methods:
Mice were then subjected to the azoxymethane/dextran sulfate sodium model of colitis and colitis-associated cancer incorporating intervention with daily injections of 0.75 mg/kg calpain-2 inhibitor beginning after the first signs of colitis.
Results:
Calpain-2 inhibitor treatment alleviated weight loss and bloody diarrhea, and reduced inflammatory infiltration into colon tissues and inflammatory cytokine mRNA. Calpain-2 inhibitor intervention also reduced total colitis-associated cancer tumor volume by up to 70% in vehicle control mice and decreased cancer pathology scores of blinded histological colon tissue analyses. Mechanistic investigations showed that calpain-2 inhibition during macrophage activation reduced inhibitor of kappa beta (IκB) degradation and nuclear factor kappa beta (NFκB) nuclear localization as well as secretion of specific inflammatory cytokines. In addition, calpain-2 inhibitor treatment of CT26.WT mouse and HT-29 human colorectal cancer cells decreased proliferation and reduced IκB degradation and NFκB translocation.
Conclusions:
Overall, these findings suggest that intervention with a calpain-2 inhibitor may reduce colitis and colitis-associated cancer through a two-hit process of limiting macrophage activation and inhibiting growth of the colorectal cancer cells themselves.
Insights
A novel calpain-2 inhibitor effectively reduced colitis and inflammation-associated colorectal cancer in mice by targeting macrophage activation and cancer cell growth. This therapeutic approach shows promise for treating inflammatory bowel diseases and associated cancers.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- Calpain enzymes, particularly calpain-2, play a crucial role in regulating inflammation and macrophage activation.
- Inflammation is a key factor in the development of colitis and associated colorectal cancer.
- There is a need for novel therapeutic strategies to manage these conditions.
Purpose of the Study:
- To evaluate the therapeutic potential of a synthetic calpain-2 inhibitor, zLLY-CH2F, in preclinical models of colitis and inflammation-associated colorectal cancer.
- To investigate the mechanisms by which calpain-2 inhibition impacts inflammatory pathways and cancer cell behavior.
Main Methods:
- Mice were induced with the azoxymethane/dextran sulfate sodium model of colitis and colitis-associated cancer.
- Mice received daily injections of the calpain-2 inhibitor (zLLY-CH2F) or vehicle control.
- Macrophage activation, inflammatory markers, tumor growth, and cancer pathology were assessed. Mechanistic studies involved analyzing IκB degradation and NFκB translocation in immune and cancer cells.
Main Results:
- Calpain-2 inhibitor treatment significantly alleviated colitis symptoms, including weight loss and bloody diarrhea.
- The inhibitor reduced inflammatory cell infiltration, inflammatory cytokine mRNA levels, and overall tumor volume in colitis-associated cancer by up to 70%.
- Mechanistically, calpain-2 inhibition suppressed IκB degradation and NFκB nuclear localization in activated macrophages and colorectal cancer cells, thereby reducing inflammatory cytokine secretion and cancer cell proliferation.
Conclusions:
- Intervention with a calpain-2 inhibitor demonstrates significant therapeutic potential for treating colitis and associated colorectal cancer.
- The dual mechanism of action involves limiting macrophage activation and directly inhibiting colorectal cancer cell growth.
- These findings support the development of calpain-2 inhibitors as a novel treatment strategy for inflammatory bowel disease and cancer.
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