I want to test antioxidant drug in spontaneous colorectal cancer mouse model. By knocking down NLRP3 inflammasome, mice which already having spontaneous colitis develops tumor in proximal colon at age 12, without giving any carcinogen. I am wondering whether my antioxidant will work on this model or not? I want to inhibit the ROS level in order to ameliorate the progression of colitis to cancer.
Hi Sonia,
To figure down your scientifically important problem of using a proper antioxidant, it is crucial to understand in your model peculiarities of a known “triangle problem” (relationships between NLRP3, macrophage ROS and tumor growth). Yes, in other models, the NLRP3 inflammasome, a protein complex controlling maturation of important pro-inflammatory cytokines interleukin (IL)-1β and IL-18, is also involved in tumorigenesis and metastasis of various cancers. However, a common denominator among the multiple damage-inducing agents that ultimately lead to activation of NLRP3 has not yet been identified. Recent study showed that ROS inhibitor such as DPI abolished IL-1β release in mouse macrophages by inhibiting NLRP3 gene expression (Bauernfeind F, et al. “Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome”. J. Immunol. 187:613–617, 2011). It was demonstrated that production of ROS has been suggested to act as a common event upstream of the NLRP3 inflammasome machinery. Because de novo translation of NLRP3 is an essential step in the activation of NLRP3, the role of substances that inhibit either ROS production or its oxidative activity was studied. Although NLRP3 inflammasome activation is unique among other known inflammasomes in its sensitivity to ROS inhibition was observed, it was found that this phenomenon is attributable to the fact that NLRP3 strictly requires priming by a proinflammatory signal, a step that is blocked by ROS inhibitors. Although these data do not exclude a general role for ROS production in the process of NLRP3-triggered inflammation and subsequent malignization, they would put ROS upstream of NLRP3 induction, but not activation.
Best regards,
Ilya
- Badges
- Science topic
- Similar topics
- Engineering
- Chemical Engineering
- Membranes