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Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation / RUISONG WANG

Swansea University Author: RUISONG WANG

DOI (Published version): 10.23889/Suthesis.51919

Abstract

Prostate cancer (PCA) is one of the most common cancers in males’ affecting the genitourinary system. Although early stage PCA can be effectively treated, therapeutic options for patients with aggressive PCA are more limited and have lesser efficacy. In recent years, aspirin has been found to be an...

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Published: 2019
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa51919
first_indexed 2019-09-16T20:20:48Z
last_indexed 2019-10-21T16:58:05Z
id cronfa51919
recordtype RisThesis
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However, its mechanism of its action is not fully understood yet. Aspirin has shown great promise in PCA and is currently being employed in clinical trials. Thus, defining aspirin&#x2019;s molecular impact on prostate cancer cells would provide valuable information to improve the clinical management of PCA patients. This thesis aimed to evaluate the consequence of aspirin exposure on cell cycle, proliferation and functional parameters of prostate cancer cells to determine aspirin&#x2019;s mechanistic role in supporting the treatment of prostate cancer patients. This thesis also established a 3D culture system to enhance our standard in vitro models applied in the evaluation of drug efficacy and toxicity. The metabolite of aspirin, salicylate, was exposed to PC3 and DU145 prostate cancer cell, and PNT2, a normal prostate cell line. Cytotoxicity analysis based upon relative population doubling (RPD), Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) for gene expression profiling and INCell Analyzer 2000 analysis for cell morphological and DNA damage assessment, were used to evaluate the cellular impact of salicylate exposure. The role of the COX-2 signalling pathway in salicylate&#x2019;s mode of action was considered by repeating salicylate exposure experiments in the presence of the inhibitor celecoxib; while activation of the NF-B pathway was also studied. To better understand the consequence of salicylate exposure on a human tumour, PC3 cell-spheroids were fabricated on agarose-coated 96 well-plates and were characterised by the MTT assay (cell viability), confocal microscopy (to assess necrosis, oxygen availability and morphology), and RT-qPCR for COX-2 expression. Salicylate was subsequently exposed to these spheroids and consequence of this treatment was established by comparing the experimental outcomes to the endpoints evaluated in 2D PC3 cell exposures. Salicylate was found to downregulate effects on growth and COX-2 gene expression; it induced morphological changes, DNA damage and cell mitochondria loss; delayed the cell cycle; and increased intracellular Ca2+ level. These effects were more prominent in the PCA cells than in PNT2 cells indicating that the cancer cells were more sensitive to salicylate toxicity than normal prostate cells. The role of salicylate in PCA was partially COX-2-dependent and NF-B-dependent. Although similar responses were noted when salicylate was exposed to PC3 cell spheroids, generally the level of response was lower than observed in the 2D PC3 cultures. The data contained within this thesis demonstrates that aspirin induces anti-cancer effects on PCA cells partially via NF-B and COX-2 mediated pathways. The 3D culture system provided an exciting and more realistic model for drug evaluation. 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spelling 2019-09-17T11:23:46.4842911 v2 51919 2019-09-16 Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation 36ca3270e1e3032b72bdb4079ae51449 RUISONG WANG RUISONG WANG true false 2019-09-16 ONDF Prostate cancer (PCA) is one of the most common cancers in males’ affecting the genitourinary system. Although early stage PCA can be effectively treated, therapeutic options for patients with aggressive PCA are more limited and have lesser efficacy. In recent years, aspirin has been found to be an effective chemo-preventative treatment for a range of cancers. However, its mechanism of its action is not fully understood yet. Aspirin has shown great promise in PCA and is currently being employed in clinical trials. Thus, defining aspirin’s molecular impact on prostate cancer cells would provide valuable information to improve the clinical management of PCA patients. This thesis aimed to evaluate the consequence of aspirin exposure on cell cycle, proliferation and functional parameters of prostate cancer cells to determine aspirin’s mechanistic role in supporting the treatment of prostate cancer patients. This thesis also established a 3D culture system to enhance our standard in vitro models applied in the evaluation of drug efficacy and toxicity. The metabolite of aspirin, salicylate, was exposed to PC3 and DU145 prostate cancer cell, and PNT2, a normal prostate cell line. Cytotoxicity analysis based upon relative population doubling (RPD), Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) for gene expression profiling and INCell Analyzer 2000 analysis for cell morphological and DNA damage assessment, were used to evaluate the cellular impact of salicylate exposure. The role of the COX-2 signalling pathway in salicylate’s mode of action was considered by repeating salicylate exposure experiments in the presence of the inhibitor celecoxib; while activation of the NF-B pathway was also studied. To better understand the consequence of salicylate exposure on a human tumour, PC3 cell-spheroids were fabricated on agarose-coated 96 well-plates and were characterised by the MTT assay (cell viability), confocal microscopy (to assess necrosis, oxygen availability and morphology), and RT-qPCR for COX-2 expression. Salicylate was subsequently exposed to these spheroids and consequence of this treatment was established by comparing the experimental outcomes to the endpoints evaluated in 2D PC3 cell exposures. Salicylate was found to downregulate effects on growth and COX-2 gene expression; it induced morphological changes, DNA damage and cell mitochondria loss; delayed the cell cycle; and increased intracellular Ca2+ level. These effects were more prominent in the PCA cells than in PNT2 cells indicating that the cancer cells were more sensitive to salicylate toxicity than normal prostate cells. The role of salicylate in PCA was partially COX-2-dependent and NF-B-dependent. Although similar responses were noted when salicylate was exposed to PC3 cell spheroids, generally the level of response was lower than observed in the 2D PC3 cultures. The data contained within this thesis demonstrates that aspirin induces anti-cancer effects on PCA cells partially via NF-B and COX-2 mediated pathways. The 3D culture system provided an exciting and more realistic model for drug evaluation. Aspirin, therefore, has significant potential value for the clinician management of PCA patients. E-Thesis Prostate cancer, aspirin, 3D culture 31 12 2019 2019-12-31 10.23889/Suthesis.51919 A selection of third party content is redacted or is partially redacted from this thesis. COLLEGE NANME Other/Subsidiary Companies - Not Defined COLLEGE CODE ONDF Swansea University Doctoral Ph.D 2019-09-17T11:23:46.4842911 2019-09-16T16:48:09.7637921 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine RUISONG WANG 1 0051919-16092019171053.pdf Wang_Ruisong_PhD_Thesis_Final_Embargoed17.07.2022_Redacted.pdf 2019-09-16T17:10:53.0700000 Output 12786619 application/pdf Redacted version - open access true 2022-07-17T00:00:00.0000000 true
title Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
spellingShingle Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
RUISONG WANG
title_short Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
title_full Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
title_fullStr Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
title_full_unstemmed Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
title_sort Sodium salicylate effects on prostate cancer aggressiveness and development of prostate cancer spheroids for drug evaluation
author_id_str_mv 36ca3270e1e3032b72bdb4079ae51449
author_id_fullname_str_mv 36ca3270e1e3032b72bdb4079ae51449_***_RUISONG WANG
author RUISONG WANG
author2 RUISONG WANG
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institution Swansea University
doi_str_mv 10.23889/Suthesis.51919
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Prostate cancer (PCA) is one of the most common cancers in males’ affecting the genitourinary system. Although early stage PCA can be effectively treated, therapeutic options for patients with aggressive PCA are more limited and have lesser efficacy. In recent years, aspirin has been found to be an effective chemo-preventative treatment for a range of cancers. However, its mechanism of its action is not fully understood yet. Aspirin has shown great promise in PCA and is currently being employed in clinical trials. Thus, defining aspirin’s molecular impact on prostate cancer cells would provide valuable information to improve the clinical management of PCA patients. This thesis aimed to evaluate the consequence of aspirin exposure on cell cycle, proliferation and functional parameters of prostate cancer cells to determine aspirin’s mechanistic role in supporting the treatment of prostate cancer patients. This thesis also established a 3D culture system to enhance our standard in vitro models applied in the evaluation of drug efficacy and toxicity. The metabolite of aspirin, salicylate, was exposed to PC3 and DU145 prostate cancer cell, and PNT2, a normal prostate cell line. Cytotoxicity analysis based upon relative population doubling (RPD), Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) for gene expression profiling and INCell Analyzer 2000 analysis for cell morphological and DNA damage assessment, were used to evaluate the cellular impact of salicylate exposure. The role of the COX-2 signalling pathway in salicylate’s mode of action was considered by repeating salicylate exposure experiments in the presence of the inhibitor celecoxib; while activation of the NF-B pathway was also studied. To better understand the consequence of salicylate exposure on a human tumour, PC3 cell-spheroids were fabricated on agarose-coated 96 well-plates and were characterised by the MTT assay (cell viability), confocal microscopy (to assess necrosis, oxygen availability and morphology), and RT-qPCR for COX-2 expression. Salicylate was subsequently exposed to these spheroids and consequence of this treatment was established by comparing the experimental outcomes to the endpoints evaluated in 2D PC3 cell exposures. Salicylate was found to downregulate effects on growth and COX-2 gene expression; it induced morphological changes, DNA damage and cell mitochondria loss; delayed the cell cycle; and increased intracellular Ca2+ level. These effects were more prominent in the PCA cells than in PNT2 cells indicating that the cancer cells were more sensitive to salicylate toxicity than normal prostate cells. The role of salicylate in PCA was partially COX-2-dependent and NF-B-dependent. Although similar responses were noted when salicylate was exposed to PC3 cell spheroids, generally the level of response was lower than observed in the 2D PC3 cultures. The data contained within this thesis demonstrates that aspirin induces anti-cancer effects on PCA cells partially via NF-B and COX-2 mediated pathways. The 3D culture system provided an exciting and more realistic model for drug evaluation. Aspirin, therefore, has significant potential value for the clinician management of PCA patients.
published_date 2019-12-31T13:54:43Z
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