Pavithran, Nevil Mallet;
(2024)
The Role of Doxazosin in Prostate and Bladder Cancers.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Doxazosin, an alpha-1 adrenergic receptor antagonist, is used to treat hypertension and benign prostatic enlargement. Additionally, it has shown antineoplastic effects on various cancers, including prostate and bladder cancer. These anticancer effects are unrelated to its alpha-adrenergic activity and are instead linked to its quinazoline-based chemical structure. The specific mechanisms and receptors involved in doxazosin's antineoplastic activity remain unclear. This study aimed to elucidate the cellular mechanisms by which doxazosin induces cell death in prostate and bladder cancer cells. Methods: Using UniProtKB/PSI-Search 2, we identified that 5- hydroxy tryptamine receptors have structural similarity to alpha-1 adrenergic receptors. Subsequently, we investigated if the antineoplastic actions of doxazosin were mediated via 5- hydroxy tryptamine due to its structural similarity to alpha-1 adrenergic receptors. In parallel, we also attempted to develop doxazosin-resistant cell lines with a view to investigate the up regulation and/or down regulation of such receptors. As both the above did not yield any results, we subsequently investigated non-receptor mediated pathways (such as endocytosis and pinocytosis). During our experiments to develop doxazosin-resistant cells, we had incidentally observed that granulations appeared within cells when exposed to doxazosin. We explored this further using SEM, TEM, and immunostaining techniques. Subsequently, we investigated the changes in gene expression following exposure to doxazosin. Finally, we conducted In Vivo experiments to ascertain if the experiments findings translated to similar actions in nude athymic mice. Results: We were able to demonstrate that dynamin-mediated and clathrin dependent endocytic trafficking of doxazosin resulted in widespread autophagy (mitophagy) in prostate, bladder and fibroblast cells undergoing cell death following exposure to doxazosin. Furthermore, doxazosin increased the gene expression of several gene families related to autophagy, apoptosis, anoikis, and lipid metabolism. Doxazosin also inhibited the growth of HT1376 bladder cancer cell implants In Vivo in nude athymic mice. Conclusion: Our results raise the possibility that doxazosin could be useful in the management of advanced urological malignancy.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of Doxazosin in Prostate and Bladder Cancers |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10193557 |
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