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Ammar, Amr Elsayed

University of British Columbia

Therapeutic use of leeching has been a popular method in traditional medicine and is being revisited recently in conventional medicine due to presence of several peptides and protein components having various medicinal benefits. In this study, we investigated the safety of using leech saliva extract from Hirudinaria manillensis (LSE) in addition to its anticancer effects in prostate cancer (PCa) xenograft model. In addition to this we studied the compositional analysis of the extract using HPLC/UV/MS. In the toxicity study, no mortality or treatment related toxicity effects were observed at the range of the studied doses. The result of LSE compositional analysis revealed 24 bioactive components. The identified components include several anticoagulants and protease inhibitors matching various compounds previously found in leech extracts. In vitro, LSE was found to be cytotoxic in five PCa cell lines and caused inhibition of markers of cell adhesion (P-cad), apoptosis (ERK1/2, p-ERK1/2) and androgen receptor (AR) expression in 22Rv1 cells, AR and PSA activation in LNCap cells. In vivo efficacy was investigated using LNCaP and 22Rv1 human xenografts representing PCa. In vivo, LSE treatment decreased tumor volume compared to control in both models, and serum Prostate specific antigen (PSA) levels in the LNCaP model. LSE treatment increased cleaved caspase-3, while it decreased p21, and CD-31 protein expression. LSE demonstrated anticancer effects which is mediated by promoting apoptosis and inhibiting angiogenesis. Additionally, we investigated protease activated receptor-1 (PAR-1) as a target of treatment in prostate cancer as recent studies have demonstrated a role of protease activated receptors in several types of cancer. In vivo PAR-1 study was divided into two groups using PC3 wild type cells and CRISPR-PAR-1 null PC3 xenografts. PC3 wild type xenograft exhibited no significant difference in tumor growth between the vorapaxar (a PAR-1 blocker) treated group and the control group, similar results were obtained in the PC3 PAR-1 null xenograft. Additionally, when comparing the control arms of both studies there was no difference in tumor volume growth indicating that PAR-1 appears not to affect prostate cancer growth directly at least as a single factor.

Text

2022-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79671

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/