Inflammation and immune response are hallmarks of cancer progression and
recurrence, and pro-inflammatory lipid mediators arising from the activity of cyclooxygenases (COX) on arachidonic acid have been more and more recognized as playing a role in the development and progression of several types of cancer, from breast and lung to prostate and colorectal cancers.
The first evidence of the role of COX-derived metabolites in oncogenesis was the tumor suppressive effect of COX inhibitors, and regular use of aspirin proved effective in reducing the risk for precancerous colorectal neoplasia and colorectal cancer (CRC). Thromboxane A2 (TW2), the main platelet-derived COX metabolite inhibited by low-dose aspirin, may therefore play a functional role in critical steps of neoplastic transformation such as tumor cells motility, invasion, and proliferation leading to cancer progression, and TXA2 signaling has been reported in prostate, breast, lung, brain, bladder and colon cancer. COX-2 plays a central role in inflammation, but is also frequently expressed at tumorigenic nests in wide variety
of cancers and both preclinical and clinical trials using COX-2 selective
inhibitors (COXIB) have been showing promising results.
Evidence of cooperation between COX-2 and T nz in cancer progression have been reported and the COX-2/TXA2 signaling pathway has been shown to modulate hepatocyte growth factor receptor (MET) activation and prevent apoptosis in cancer cells resistant to tyrosine kinase inhibitors. Enhanced residual systemic TXA2 biosynthesis can be observed also in presence of low dose aspirin treatment, suggesting that, together with enhanced prostaglandin(PG)E2 biosynthesis insensitive to low-dose Aspirin, residual TXAz formation may play a role in the variability of the antitumoi efficacy of the drug detected in randomized clinical studies with FAP patients and in the increased cancer mortality observed in healthy elderly who received daily aspirin. Novel chemotherapeutic strategies should involve inhibiting
extraplatelet TXA2 generation and/or blocking its biological effects. We developed a novel class of Non-steroida1 anti-inflammatory drugs (NSAIDs)
that can selectively inhibit COX-2 and antagonize TXA2 receptor (TPR) in a slngle, bifunctional molecule. Convincing in vitro data provide proof-of- concept evidence of compounds which antagonize TPR and selectively inhibit COX-2 activity in the high nanoinolar range have been obtained, and therefore we propose to assess the best developed molecules in a variety of in vitro and in vivo models to define their potential application for the chemoprevention of selected forms of CRC and hepatocellular carcinoma (HCC).