New synergic biomaterials for anti-cancer therapy
- Authors: Swanepoel, Bresler
- Date: 2019
- Subjects: Pharmaceutical chemistry , Cancer -- Research , Biomedical materials
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/43957 , vital:37087
- Description: In the last two decades, anti-cancer therapy has grown considerably with the help of both natural and synthetic anti-cancer compounds but, the search for new and improved cancer treatment remains an ongoing and important issue. Some anti-cancer compounds such as cisplatin are limited by their toxicity in normal tissues and the development of drug resistance. Therefore, in order to address drug resistance and side-effects of anti-cancer agents, recent research has been focusing on finding novel combinations of anti-cancer agents that have non-overlapping mechanisms of action. The first objective of this study was to determine the mechanism of action of Anemone nemorosa, Artemisia afra, N-[[3-(4-bromophenyl)-1H-pyrazol-5-yl]-carbamothioyl]-4-chloro-benzamide (BC-7) and N-benzoyl-N’-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-thiourea (BT-7) through cell cycle arrest, phosphatidylserine translocation (PS), caspase activation and mitochondrial membrane depolarization. This study has shown that A. nemorosa, BC-7 and A. afra are capable of inducing cell death within three cancer cell lines namely HeLa, MeWo and HepG2, at varying degrees. HeLa cells were the most susceptible to treatment with A. nemorosa and BC-7 with IC50 values of 20.33 ± 2.480 μg/ml and 65.58 ± 8.400 μM (28.58 ± 3.660 μg/ml), respectively. A. afra was the most active against HepG2 cells with an IC50 value of 37.55 μg/ml. BT-7 was not cytotoxic against any of the cancer cell lines. The effects on HeLa cells and their progression through the cell cycle indicated that cells were arrested in the early M phase for all treatments. The induction of apoptosis was confirmed by an increase in PS translocation and activation of caspase 3 and 8 as well as a decrease in the mitochondrial membrane potential. It was deduced that A. nemorosa, A. afra and BC-7 induce caspase-dependent apoptosis in a mitochondrial dependent manner. The second objective of this study was to investigate the potential of A. nemorosa, A. afra and BC-7 to target various mediators involved in the inflammatory response as an alternative method in which cell death may be induced. Most treatments indicated that a tumour-elicited inflammatory response is indeed induced in HeLa cells and that the significant activation of nuclear factor kappa B (NF-κB) favoured the production of nitric oxide (NO) over cyclo-oxygenase 2 (COX-2). However, treatments with A. nemorosa, BC-7 and A. afra at their IC10 showed the potential of inhibiting this response. ROS levels were increased by most treatments and support the idea of ROS-mediated apoptosis. The third objective was to investigate combination treatments of these extracts and compounds for their potential synergistic cytotoxic activity and thus formulating the combinations as potential anti-cancer agents. Thirty combination mixtures were prepared using the IC50 values of each extract or compound at ratios of 1:3, 1:2, 1:1, 2:1 and 3:1, respectively. The cytotoxic/anti-proliferative activity of each mixture was determined by the bisBenzamide H 33342 trihydrochloride/propidium iodide (Hoechst 33342/PI) dual staining method on HeLa cervical cancer cells. The combination index (CI) values, at inhibition of 50% of HeLa cell growth, for each combination mixture, were determined by means of the Chou and Talalay method. The combined effect can then be indicated as CI < 1, synergism; CI = 1, additive effect or CI > 1, antagonism, respectively. Most combination treatments showed to have an antagonistic effect except for cisplatin:BC-7 (1:3, 1:1, 2:1, 3:1) and cisplatin:A. afra (1:3, 1:2, 1:1, 3:1) combinations that showed synergism. The 1:2 ratio of cisplatin:BC-7 and the 2:1 ratio of cisplatin:A. afra were additive. CI values were also calculated at inhibition of 10, 25 and 75% of HeLa cell growth, for each combination mixture. Antagonistic effects were frequently observed at lower effect levels such as at 10 and 25% inhibition of growth. However, this was not seen for the cisplatin:BC-7 combinations as all the ratios indicated synergism. Some of these ratios, such as the 1:3 and 1:2, even led to a greater degree of synergism being obtained, with noticeable antagonistic effects seen at 50 and 75% inhibition of growth. The current finding is that BC-7 and A. afra could lower the dose of cisplatin in combination to achieve a similar anti-cancer efficacy compared to the higher cisplatin dose when used alone. The lower dosage in combination could result in reduced drug resistance as well as limit the toxicity on normal cells associated with cisplatin treatment. In conclusion, this study shows, for the first time, that A. nemorosa has the potential to induce apoptosis and also has some anti- and pro-inflammatory activity in HeLa cancer cells. This study also enhanced the knowledge of the mechanism of apoptosis induction of BC-7, in a more detailed manner, as well as investigated its inflammatory effects for the first time. Results obtained for A. afra correlated nicely to previously reported studies and confirmed that the methods used in this study, although different, leads to the same conclusions. Combination treatments also indicated, for the first time, that BC-7 and A. afra have the ability to function in a synergic manner with cisplatin and proves that, although extensive research may have been done on a plant or compound, more can be discovered. This new information can lead to identification of new compounds in the plants and the integration of signalling pathways that can be targeted for treatment of cancer.
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- Date Issued: 2019
The relationship between altruistic behaviour, emotional intelligence and intrinsic motivation amongst leaders
- Authors: Hooper, Danushka
- Date: 2017
- Subjects: Intrinsic motivation -- Leadership Emotional intelligence , Employee motivation Leadership
- Language: English
- Type: Thesis , Masters , MA
- Identifier: http://hdl.handle.net/10948/15978 , vital:28299
- Description: The benefits that altruistic behaviours, emotional intelligence (EQ) and intrinsic motivation have on organisations are increasingly becoming observable and enticing greater insights into these constructs, especially from the perspective of leaders. Moreover, the increase in the effectiveness of leaders across all of these constructs enables greater employee performance, from both the perspective of leaders and their followers, which results in increased organisational profitability. The primary objective of this research study was to investigate the relationship between the three constructs of altruistic behaviour, EQ and intrinsic motivation amongst leaders in South African organisations. This study also attempted to determine whether intrinsic motivation has a mediating effect on EQ and altruistic behaviours. Moreover, this study wishes to identify demographic differences in terms of the responses to the items related to each of the constructs. The questionnaires employed by this study was administered to leaders (n=136) who currently work in South Africa. Positive and statistically significant relationships were found amongst these constructs, implying that, an increase in one of these constructs will result in an increase in another. However, there was no sufficient evidence in support of mediating effect of intrinsic motivation on EQ and altruistic behaviours. The confirmatory factor analysis was able to validate all three measuring instruments used to assess the constructs from a South African perspective. The present study was unable to identify any demographic differences for the Adapted Self-Report Altruism Scale and Intrinsic Work Motivation Scale and was only able to identify demographic differences by the Schutte Self-report Emotional Intelligence Test as a whole and the perception of emotion scale. The study encountered some limitations. Firstly, the researcher encountered a difficulty in finding appropriate literature on the constructs. Secondly, the study obtained a small sample size (n=136). The reason for this is that the target sample chosen by the researcher, namely leaders in organisations, proved to be a challenging sample because many leaders were not able or willing to complete the questionnaire due to their heavy workload and strict deadlines. Thirdly, given that three measuring instruments were used to gain the data needed for this study, the total number of items came to 136. This could mean that the questionnaire may have been burdensome to complete and it would take approximately 15 minutes to complete. In addition, factors such as biased responses, as well as personal and environmental factors on the part of the respondents all posed limitations to this study in that it may have influenced the responses given by the sample. The results obtained by this study suggests that the higher the level of EQ of leaders, the higher the likelihood that they will be intrinsically motivated and exhibit altruistic behaviour. As explained by exchange theory, if one is conditioned to be “good”, the likelihood of partaking in altruistic behaviour is enhanced (Bar-Tal, 1986). If an organisation creates a culture of altruistically helping others in the workplace and the community, the possibility of creating a “habit” of exhibiting altruistic behaviour could result. The benefits of creating this altruistic culture could be far-reaching. The researcher encourages organisations to measure and identify the level of EQ of their leaders and provide development opportunities should this be lacking. This is because, as identified by Barbuto and Burbach (2006), in order for leaders to achieve support from their followers, it is crucial that they develop a high reliance on their empathy to identify with the feelings and emotions of their followers. It is important to note that the results of this study was analysed in June 2016 and is based only on 136 leaders across some industries of South Africa. It is suggested that the results of this study to be validated in the South African context by additional empirical research that tests the hypothesis identified in this study to ascertain whether the results of the current study can be replicated and applied broadly. It is advised that the study is tested over a longer period, in different industries and across various countries. This is so that increasing value can be added to this field of research.
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- Date Issued: 2017