Discussion The association between cancer and inflammation is well established. However, the mechanisms that govern this association are not well understood. Two notions have been put forth http://www.selleckchem.com/products/CHIR-258.html to help explain this phenomenon one posits that the carcinogenic nature of activated inflammatory cells initiates transforming mutations while another suggests that inflammation is a response to neo plastic transformation and is responsible for tumor pro gression. Histochemical analyses often used to characterize the actions of inflammatory cells at cancer sites may not provide a complete look into the complexi ties of how the tumor microenvironment is operating. In recent years, several groups have demonstrated acti vation of the RET/PTC oncogene in the thyroids of humans with autoimmune thyroiditis without thyroid cancer.

In such cases, the relationship between cancer and inflammation could instead be interpreted with a view that oncogenic transformation is the basis for the observed inflammation. Along these lines, RET/PTC3 can induce pro inflammatory activities from thyroid epithelial cells, and thus inhibi tion of such inflammation may have implications for dis ease control. Farnesyltransferase inhibitors are a class of small mole cule agents developed as a novel approach to anti cancer treatment, designed to target a post translational modifi cation required for functionality of certain membrane associated proteins, including RAS. These molecules were targeted based on evidence that many human cancers con tain mutations of RAS proteins.

Although clinical trials of farnesyltransferase inhibitors demonstrated low toxicity, clinical efficacy was also low in several malignancies. Some scientists have postulated that this may be due to a lack of Ras signaling in later stages of tumor development, while others look to alternate pathways potentially affected by off or on target effects of FTI. These failures notwithstanding, more recent data has demonstrated effi cacy of FTI as an anti inflammatory agent in both cell and animal based models of inflammation. FTI activ ity has been shown to inhibit the expression of NF?B as well as pro inflammatory cytokines such as Ccl2, Il6, and Ifn? induced by carcinogens and inflammatory stimuli. We have shown here that clinically relevant nanomolar doses of FTI significantly reduce the expression of pro inflammatory mediators Ccl2 and Cxcl1, shown to be two of the chemokines most highly induced by RP3.

We further demonstrate that this reduction is not due to a similarly decreased expression of the oncogene itself. FTI is likely Carfilzomib acting post translationally. We postulate that the effects we have demonstrated with these experiments are due to FTI acting to block selleck products RP3 signaling through the RAS pathway, inhibiting NF?B activation, and resulting in decreased expression of pro inflammatory mediators.