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Title: The role of serotonin (5HT) and 5HT antagonists in urological cancers
Author: Siddiqui, Emad Jawed
ISNI:       0000 0001 3408 7536
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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Neuroendocrine (NE) differentiation takes place in both prostate and bladder cancer tissue. These NE cells release growth factors including neuropeptides and biogenic amines which correlate with tumour progression, differentiation, androgen independence, angiogenesis and poor prognosis. Serotonin (5-hydroxytryptamine 5HT), a monoamine neurotransmitter, plays a role in regulation of growth, gene expression and may function as a proto- oncogene. 5HT acts as a growth factor in tumours such as small cell carcinoma of the lung and colonic carcinoma. The in vitro effect of 5HT and 5HT antagonists on prostate and bladder cancer cell growth was evaluated. Cell culture and proliferation assay studies established a significant increase in growth proliferation by 5HT. Furthermore, there was a significant growth inhibition by 5HTiA and 5HTiB antagonists on prostate cancer (PC3) cells and bladder cancer (HT1376) cells. FACS analysis in PC3 cells demonstrated cell cycle arrest and apoptosis when treated with 5HTia and 5HTib antagonists. Immuno-staining for 5HT- A and 5HT-ib receptors was seen in PC3 cells, HT1376 cells, as well as in human prostate and bladder cancer tissue. Western blot analysis demonstrated 5HT-IA and 5HT1B receptor proteins in both prostate and bladder cancer cells and tissue. Ethical approval was obtained and the Helsinki Declaration of Human Rights was strictly adhered to throughout this study. These results imply that a 5HT system exists in both prostate and bladder cancer tissue. 5HTia, and in particular 5HT1B receptor antagonists, warrant further investigation as potential anti-neoplastic agents. A growth inhibitory effect of an alpha adrenoceptor antagonist (doxazosin) on PC3 and HT1376 cells was also demonstrated. This growth inhibition is independent of the antagonist action on alphai-adrenoceptors. Incubation of PC3 cells with 5HT or 5HTib agonist partially reversed the growth inhibitory effect of doxazosin. Doxazosin may modulate the action of 5HT, possibly at the receptor level. Doxazosin (or more effective analogues) commonly used in the treatment of benign prostatic hyperplasia, may be potential chemotherapeutic agents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available