Regulation of NLRP3 inflammasome and Caspase-3/4/11 by 2',4'-dihydroxychalcone contributes to anti-colorectal cancer.

Abstract

Background: Chronic inflammation is closely related to the occurrence and progression of many cancers, especially colorectal cancer (CRC), which can be triggered by repeated and sustained induction of colitis in mice. CRC is a typical type of cancer that can be caused by inflammation and NLRP3 inflammasome dysregulation plays a certain role in the pathogenesis of CRC.

Purpose: As an edible Chinese medicine, Abrus cantoniensis Hance (ACH) has both anti-inflammatory and anti-tumor activities. However, most research has focused on inflammation-related diseases, and less research has been done on its active ingredients and targets and its application in CRC. Here, this study deeply explored the target of 2',4'-DHC and its pharmacological mechanism in anti-colon cancer, and provided a new strategy for its drug development and treatment of colon cancer.

Methods: The cytotoxicity of ACH's active ingredient in HT29 and CT26 cells was measured by CCK-8, clone formation, apoptosis, and cell cycle assay. The metastasis inhibition of CRC cells was determined by wound-healing assay. Western blotting was used to detect the NLRP3 inflammasome activation, pyroptosis, and apoptosis activation. Finally, the in vivo efficacy of 2',4'-DHC was verified by establishing CT26 and HT29 tumor transplant models in mice.

Results: Here, our study firstly demonstrated that 2',4'-DHC inhibited the growth of CRC cells mainly by increasing CRC cell death and ameliorating tumor immunosuppressive environment, which is verified by inducing apoptosis and pyroptosis by regulating caspase-3/4/11, arresting cell cycle in G2/M phase, suppressing the migration of CRC cells, and inhibiting NLRP3 inflammasome activation through inhibiting the NF-κB pathway, enhancing the anticancer immune response by increasing the infiltration of T cells and function of CD8⁺ cytotoxic T cells but decreasing the infiltration of CD11b⁺ CD206⁺ macrophages and function. Importantly, the administration of 2',4'-DHC decreased liver and spleen indexs to mice's normal levels and reduced the burden of CT26 and HT29 tumor-bearing in mice without pathological changes in the major organs.

Conclusion: 2',4'-DHC inhibited CRC growth through various mechanisms, mainly by regulating NLRP3 inflammasome and caspase-3/4/11 activation. Considering the anti-tumor and immunomodulation roles of 2',4'-DHC, it might be a new direction for the development of new strategies to treat colorectal cancer.