Explorative studies to understand if aldehyde dehydrogenase (ALDH) expression in colon cancer can be exploited as a target for therapeutic intervention. Expression profiling of ALDH7A1 in colorectal cancer
Colorectal cancer (CRC) has been one of the leading causes of cancer related deaths worldwide. CRC patients with recurrent or metastatic disease remain difficult to treat with current treatment options. Aldehyde dehydrogenases (ALDHs) are enzymes that play key roles in protecting cells against aldehyde-generated toxicity. Specific isoforms are also known to contribute to disease development. Emerging evidence suggests that specific ALDH isoforms might also be important for biomarker or drug discovery in CRC. The current thesis is focused on evaluating ALDH7A1 and other isoforms in patient samples while also investigating a novel library of naphthalimide-based compounds with potential to be used as hypoxia activated prodrugs (HAPs, and longer term as ALDH-targeting fluorescent probes. The current study is the first study to compare both Nigerian and UK patients with CRC disease. Interestingly, however, results showed ALDH7A1, and GLUT-1 were co-expressed in CRC xenografts and tissue microarrays (TMAs) revealing hypoxia also impacts on ALDH7A1 expression in clinical samples. Both ALDH1B1 and ALDH7A1 were shown to be highly expressed in all patient samples, however, in-depth mechanistic studies are required to fully elucidate the role of ALDHs in CRC. Investigation of naphthalimide-based compounds including the anticancer agents amonafide and mitonafide (MITO) were carried out to understand the cytotoxic potency under both normoxic and hypoxic conditions. Only a few compounds were soluble in water and could undergo biological testing, which limited the structure-activity relationship studies. CD-10 was explored with MITO to develop a formulation to overcome the solubility issues. Studies presented in this thesis show for the first time that liposomes can be used to encapsulate naphthalimide compounds, providing an opportunity for investigating all compounds in the naphthalimide library in future studies. In summary, the data in this thesis support the need for further studies to explore aldehyde dehydrogenase (ALDH) and its expression in CRC and whether it can be exploited as target for biomarker or drug discovery.
Colorectal cancer (CRC), Hypoxia-activated prodrug, Aldehyde dehydrogenase (ALDH), ALDH7A1, GLUT-1, Liposomes
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