Abstract
Cyclooxygenase-2 (COX-2) enzyme has been involved in the tumorigenesis and in the progression of colorectal cancer (CRC). The use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors has been proposed for the prevention and the treatment of this relevant neoplastic disease. In the light of an innovative alternative to these pharmacological approaches, we review here the possible strategies to achieve a strong and selective inhibition of COX-2 enzyme by using the mechanism of RNA Interference (RNAi) targeted against its mRNA. Anti-COX-2 siRNA molecules (siCOX-2) can be generated in CRC cells from short hairpin RNA (shRNA) precursors, delivered in vitro by a retroviral expression system, and induce a significant and stable silencing of overexpressed COX-2 in human colon cancer cells. As a safer alternative to viral approach, nonpathogenic bacteria (E. coli) can be engineered to invade eukaryotic cells and to generate siCOX-2 molecules in cancer cells. Moreover, the involvement of miRNAs in COX-2 posttranscriptional regulation opens up the possibility to exploit an endogenous silencing mechanism to knockdown overexpressed COX-2. Thus, these recent strategies disclose new challenging perspectives for the development of clinically compatible siRNA or miRNA capable of selectively inhibiting COX-2 enzyme.
Highlights
We recently reported the inverse correlation between COX2 and miR-101 expression in colon cancer cell lines and we demonstrated in vitro the direct inhibition of COX-2 mRNA translation mediated by miR-101
Considering the recent literature regarding the application of RNA Interference (RNAi)-based strategies to modulate gene expression and the study of miRNAs-mediated COX-2 silencing, new COX2 selective inhibitors based on small interfering RNAs (siRNAs) or miRNA molecules could be developed
We suggest that anti-COX2 siRNAs and/or miRNAs may represent innovative tools for COX-2 silencing, especially in colorectal cancer (CRC) therapy
Summary
COX-1 isoenzyme is expressed at the same basal level in both normal and tumor tissues These findings have been confirmed analyzing many tumors including pancreas, skin, gastric, bladder, lung, head, and neck cancers [8], suggesting that COX-2, but not COX-1, may play a pivotal role in tumor formation and growth. The cancer chemopreventive activity of NSAIDs has been supported by epidemiological studies performed on humans taking aspirin and other NSAIDs on a regular basis. These studies demonstrate that incidence of various cancers, including colon, intestinal, gastric, breast, and bladder cancers, is reduced up to 40–50% [8]. The cardiovascular toxicity of rofecoxib could be increased by its capability to directly inhibit prostacyclin synthase activity, as demonstrated by our group [25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
