The Pro-Tumor and Anti-Tumor Effects of NLRP3 Inflammasome as a New Therapeutic Option for Colon Cancer: A Meta-Analysis of Pre-Clinical Studies

Abstract

Summary: IL-1b secretion is dependent on the assembly and activation of the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome has been suggested to require two signals. The first (S1) is provided by toll-like-receptor (TLR)-mediated NF-kappa activation and triggers the synthesis of the IL-1B precursor and assembly of NLRP3. The second (S2) can be mediated by danger signals such as stimulation of the purinergic P2X7 receptor by ATP or other stimuli leading to potassium efflux. High dose MBZ (10 lM) may activate both signals whereas low concentrations (1 lM) only can activate S2, potentially through purinergic receptors (P2R). High dose MBZ can induce S1 by activating TLR 8. Objectives: Therefore, in this review, we aimed to elaborate on these findings and explore how NLRP3 inflammasome affect CRC and which mechanism could be a potential therapeutic target. Methods: We systematically searched major indexing databases, including Pubmed/Medline, ISI web of science (WOS), Scopus, EMBASE, and Cochrane central, using standard terms without any language, study region or type restrictions. We collected information regarding all outcome measures, including assessment of IL-1β, TNF-α, IL-18, histological scoring, clinical scoring, and survival rate from animal tissue. Results: Of the 438 studies found through initial searches, 12 met the inclusion criteria. After applying the exclusion criteria, the main properties of 12 articles on 384 animals included in this meta-analysis. Of 12, eight were about anti-tumoral effect, and four were on pro-tumoral effect of inflammasome. The analysis revealed that NLPR3 inflammasome reduced TNFα (SMD:-3.75, 95% CI: -4.49, -3.02, P<0.00001, I2=10%), IL-1β (SMD:-4.65, 95% CI: -6.15, -3.16, P <0.00001, I2=62%), and IL-18 (SMD:-4.20, 95% CI: -6.42, -1.97, P =0.0002, I2=88%) significantly compared with the wild type mice. Conclusion: To translate anti-NLRP3-based anticancer agents from the bench to the bedside, it will be important not only to identify molecules that selectively target NLRP3 or its downstream pathways in malignant cells but also to consider the metabolic heterogeneity of these malignant cells and the mechanisms through which such heterogeneity is connected to cancer. Additional studies to disentangle the molecular and functional complexity of this network are urgently awaited. Funding Information: None. Declaration of Interests: None.