Bismuth-NSAIDs as colorectal cancer chemopreventives

Australia has one of the highest incidence rates of colorectal cancer globally. The overexpression of cyclooxygenase-2 (COX-2), an enzyme involved in the inflammatory response, has been linked to several cancer types, including colorectal cancer. COX-2 impacts numerous downstream molecular pathways, leading to several advantageous traits that promote the growth of cancer cells. Consequently, chronic inflammation is a risk factor that has been linked to the development of colorectal cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2 and numerous animal, epidemiological, and clinical studies have demonstrated that that the long-term administration of NSAIDs can prevent the development (i.e., act as chemopreventive agents) of colorectal cancer. Unfortunately, NSAIDs also inhibit COX-1, whereby the prolonged, daily administration of NSAIDs has been linked to numerous gastrointestinal (GI) side effects, such as ulceration and bleeding. Bismuth is a group 15 post-transition metal that is used in many common formulations for the treatment of GI ailments, including dyspepsia, and gastric and duodenal ulcers. Consequently, it is hypothesised that the combination of NSAIDs and bismuth in a single compound, a BiNSAID complex, could allow for the chemopreventive actions of the NSAID while combatting the associated GI side-effects. The aim of this Thesis was to investigate the potential of a series of BiNSAIDs of the general formula [Bi(L3)] (where L = tolfenamate (tolf), mefenamate (mef), indomethacin (indo) or aspirinate (asp)) as chemopreventives for colorectal cancer and compare this to the free NSAIDs, tolfH, mefH, indoH, and aspH. This was done at a fundamental level, investigating the interactions with lipid membrane mimics, at an in vitro level, where the cellular effects were explored, and finally in vivo, using a chemically induced mouse model of colorectal cancer.