The mechanism of action of captopril in human renal cell carcinoma

Reid, Janet Louise. (2003). The mechanism of action of captopril in human renal cell carcinoma PhD Thesis, The School of Medicine, The University of Queensland.

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Author Reid, Janet Louise.
Thesis Title The mechanism of action of captopril in human renal cell carcinoma
School, Centre or Institute The School of Medicine
Institution The University of Queensland
Publication date 2003
Thesis type PhD Thesis
Supervisor Dr Julie Jonsson
A/Prof David Nicol
Total pages 187
Language eng
Subjects 11 Medical and Health Sciences
Formatted abstract
The principle aim of the studies described in this thesis were to ascertain the mechanism of action of the angiotensin-converting enzyme (ACE) inhibitor, captopril, on the growth and development of human renal cell carcinoma (RCC).

Captopril significantly reduces tumour growth in a xenograft model of human RCC. However, the mechanism of action of captopril is yet to be elucidated since ACE is able to catalyse the cleavage of substrates other than angiotensin I, and captopril may also influence the activity of enzymes other than ACE.

The direct effect of chronic captopril treatment on the in vitro proliferation of human RCC cells under normoxic and hypoxic conditions was examined. Hypoxic conditions produced an upregulation in the proliferation of RCC cells. However, chronic captopril treatment did not significantly inhibit cell proliferation under normoxic or hypoxic conditions.

The contribution of the renin-angiotensin system (RAS) to the inhibition of tumour growth by captopril was investigated with the use of the additional ACE-inhibitors, enalapril and ramipril, and the angiotensin II receptor blockers (ARBs), candesartan and losartan. Sub-capsular inoculation of the human RCC cell line SN12K-1 into the left kidney of severe combined immunodeficient (SCID) mice resulted in the development of large tumours. Captopril and candesartan-treatment of mice produced a significant reduction in tumour development.

A semi-quantitative RT-PCR (polymerase chain reaction) technique was used to assess the influence of RAS-inhibition on the expression of angiogenic and immunomodulatory cytokines and receptors that have been implicated in angiogenesis and tumour growth.

Captopril, enalapril and candesartan were found to have no effect on the in vivo expression of vascular endothelial growth factor (VEGF). RAS-inhibition did however influence the VEGF receptors, KDR (kinase insert domain receptor) and Flt-1 (fms-like tyrosine kinase-1), with all three drugs significantly inhibiting the expression of KDR and captopril producing a trend supporting the increased regulation of Flt-1.

The expression and activity of matrix metalloproteinases (MMPs) was determined in xenograft tumour and normal kidney samples from untreated and captopril, enalapril and candesartan-treated mice. In vivo expression of MMP-9 in xenograft tumour was inhibited by enalapril and candesartan treatment, while MMP-2 expression was not influenced by RAS-inhibition. MMP activity was assessed using a gelatin zymography technique. MMP activity was found to be upregulated in tumour samples when compared with normal kidney tissue, while captopril alone was able to significantly inhibit the total activity of MMPs in tumour tissue.

Thus, it would appear that a number of mechanisms may contribute to the tumour inhibitory effects of captopril. RAS-inhibition is likely to have a primary role, since the ARB, candesartan was also able to produce significant tumour inhibition in the xenograft model of human RCC. The association of differential VEGF-receptor and MMP gene expression with reduced tumour growth highlights the importance of angiogenic processes in RCC. The ability of captopril, but not other RAS-inhibitors to inhibit total MMP functional activity implies a role for MMP-inhibition in the tumour inhibitory actions of the ACE-inhibitor, and may warrant further investigation into the actions of MMP inhibitors on human RCC.
Keyword Captopril
Angiotensin converting enzyme -- Inhibitors

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Wed, 13 Jul 2011, 13:44:21 EST by Ning Jing on behalf of The University of Queensland Library