Photodynamic therapy (PDT) in human epithelial and myometrial multidrug resistant tumor cell models

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Photodynamic therapy (PDT) in human epithelial and myometrial multidrug resistant tumor cell models

 

Author: Chu, Shihng Meir Ellie
Title: Photodynamic therapy (PDT) in human epithelial and myometrial multidrug resistant tumor cell models
Degree: Ph.D.
Year: 2008
Subject: Hong Kong Polytechnic University -- Dissertations
Tumors -- Photochemotherapy
Department: Dept. of Health Technology and Informatics
Pages: xxv, 267 leaves : ill. (some col.) ; 30 cm.
InnoPac Record: http://library.polyu.edu.hk/record=b2392609
URI: http://theses.lib.polyu.edu.hk/handle/200/5927
Abstract: Photodynamic therapy (PDT) is an approved cancer regimen in the USA, European Union, Japan and China. It is an alternative treatment for tumors resistant to chemotherapy and radiotherapy. In-depth investigations of it are still underway. PDT involves the combination of a light-activated photosensitiser that, in the presence of oxygen leads to the generation of reactive oxygen species for tumor cell eradication. This study aims to determine the photodynamic efficacy and cellular responses to 5-aminolevulinic acid (5-ALA)-and 5-ALA hexylester (hexyl-ALA)-mediated PDT in epithelial and myometrial multidrug resistant (MDR) tumor cell models. The cellular responses, including cell death mechanism, the anti-metastatic effect, and the signal pathways triggered by both photosensitizers (PSs), were investigated. Apart from these, the recognition of telomerase as a potential target for monitoring PDT was also addressed. For the epithelial tumor cell models, a poorly differentiated squamous nasopharyngeal carcinoma (NPC) and a human medulloblastoma (MED) cell line were used. The drug uptake, phototoxicity, the cell death mechanism, and the modulation of metastatic proteins mediated by 5-ALA-and hexyl-ALA-PDT were comparatively studied. The two PSs demonstrated apoptotic cell death and anti-metastatic effect by suppressing the metastatic protein, matrix metalloproteinases-2 (MMP-2), in both cell lines. The human telomerase reverse transcriptase (hTERT -a catalytic subunit of telomerase) mRNA expression was significantly down-regulated. The hexyl-ALA was identified as a superior photosensitizer in these tumor cells; therefore, hexyl-ALA was selected for subsequent studies.
For the myometrial tumor cell model, a poorly differentiated MDR human uterine sarcoma cells with p-glycoprotein over-expressed (P-gp -the drug efflux pump encoded by MDR1 gene) and its parental counterpart were employed. Evidently, hexyl-ALA-PDT selectively suppressed the transcription of MDR1 mRNA and, in turn, lowered the functional activity of P-gp in the MDR human uterine sarcoma cell line. Hexyl-ALA-PDT initiated apoptosis via the activation of p38 MAPK (mitogen-activated protein kinases) and JNK (c-Jun N-terminal kinase) kinases signal pathways in both uterine sarcoma cells. The anti-metastatic effect was also demonstrated. There was a reduction of hTERT mRNA and telomerase at transcriptional, translational and functional levels after treatment. The present study has revealed the underlining cellular and molecular mechanisms of hexyl-ALA and 5-ALA induced cell death for both epithelial and myometrial MDR tumor cell models. Our pioneering findings include the hTERT mRNA and telomerase can serve as pivotal markers for monitoring PDT intervention, and hexyl-ALA-PDT shows no genotoxic effect at dark and low doses in normal human lymphocytes, manifesting it to be a desirable cancer regime. Further investigations are warranted for the benefit of clinical applications in MDR tumors of different origins.

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