Investigation of chemoresistant mechanisms in triple negative breast
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AuthorsTawari, Erebi Patricia
MetadataShow full item record
AbstractCancer a global epidemic is a major cause of morbidity and mortality affecting populations in all nations and regions. Breast cancer (BC) is the second most common cancer in the world and the most fatal malignancy affecting women both in the developed and developing countries. Even with the improvement in overall survival of BC patients due to early detection and advancement with systematic therapy, triple negative breast cancer (TNBC), an aggressive subtype of BC still remains a major challenge as it lacks targetable receptors. Chemotherapy is the main treatment for TNBC. However, de novo and acquired resistance to conventional anticancer drugs is a major limitation and cause of therapeutic failure. Cancer stem cells (CSCs) are believed to be responsible for chemoresistance and tumour relapse. My study demonstrates that hypoxia is involved in the development and maintenance of these CSCs traits in TNBC, as cells grown in hypoxia are significantly resistant to several first line anti-BC drugs. Hypoxia-induced activation of nuclear factor kappa B (NFB) and hypoxia inducible factors (HIFs) also play pivotal roles in chemoresistance. Forced expression of NFB and HIFs by transfection with p65 subunits of NFB and HIF1α and 2α subunits induced CSCs characters and resistance to a range of anticancer drugs in TNBC cell lines. My study also indicated a positive loop between the activation of NFB and HIFs. Therefore development of novel medicine to interfere the pathways of hypoxia and NFB may efficaciously target CSCs and reverse chemoresistance which will be of clinical significance for TNBC treatment. iv Disulfiram (DS) is a commercially available anti-alcoholism drug. Recent studies demonstrate that it is highly cytotoxic in a wide range of cancer types and potentially repurposed as an anticancer drug. The anticancer mechanisms of DS were investigated in this study. The results from my study indicate that the cytotoxicity of DS is copper (Cu) dependent with a biphasic manner. The instant cytotoxic phase is induced by the extracellular reactive oxygen species (ROS) generated by the reaction between DS and Cu. The delayed killing is caused by the complex diethyldithiocarbamate (DDC) and Cu (DDC-Cu), the final product of the reaction. The cytotoxicity of both phases needs the intact DS. However, due to the extremely short half-life of DS in the bloodstream, the anticancer efficacy of DS has been severely hampered in vivo and in patients. Nanotechnology-based drug delivery system is a rapidly evolving and expanding interdisciplinary field involving in an amalgamation of chemistry, engineering, biology and medicine. In the last part of my study, I have successfully encapsulated DS into polymeric micelle (PM) nanoparticles. The half-life of PM encapsulated DS (PM-DS) was extended to over 3 hours in horse serum. The PM-DS showed strong anticancer efficacy. Therefore this nano-enabled DS may be able to translate DS into cancer therapeutics in the future
DescriptionA Thesis Submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.