Investigation of the anti-breast cancer efficacy and mechanisms of disulfiram
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AbstractI Abstract Cancer is a major cause of morbidity and mortality affecting populations in all countries and all regions. Breast cancer (BC) is the second leading cause of cancer death among women in the UK. Although the overall survival of BC has been significantly improved due to systemic therapy in early BC, the treatment of advanced/metastatic BC remains a major challenge. The main limitation of therapeutic failure is the de novo and acquired resistance of BC cells to conventional anticancer drugs. Cancer stem cells (CSCs) have been thought to be responsible for the chemoresistance. My study demonstrated that mammospheres manifested CSC characteristics and are highly resistant to several first line anti-BC drugs. This may be due to the hypoxia in the centre of the spheres. Transfection of BC cells with NFκB p65 induces CSC characters and chemoresistance. Therefore hypoxia-induced activation of NFκB could lead to escape of CSCs from apoptosis and regenerate the tumour after conventional chemotherapy. In clinic, the relapsed cancer is commonly pan-resistant to various drugs. Development of CSCs-targeting drug will be significantly important in clinic for cancer patients. Disulfiram (DS) is a commercially available anti-alcoholism drug with strong cytotoxicity in a wide range of cancer types and has a reversing II effect on chemoresistance. In this study, the anticancer efficacy of DS on cancer cell lines and CSCs was investigated. DS was highly cytotoxic to BC cell lines in vitro in a copper (Cu)-dependent manner. CI-isobologram analysis demonstrated a synergistic effect between DS/Cu and paclitaxel (PAC) in BC cell lines. DS/Cu induces reactive oxygen species (ROS), activates JNK and p38 pathways and simultaneously inhibits NFκB activity in BC cell lines. DS/Cu may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. The in vitro clonogenicity and sphere-forming ability of BC cell lines were inhibited by DS/Cu. The common stem cell markers such as aldehyde dehydrogenase (ALDH) and CD24-/CD44+ as well as Nanog, Sox2, and Oct4 were also suppressed. In PAC resistant cell line, DS abolished CSC characters and completely reversed PAC resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted CSC population in vivo and showed very strong anticancer efficacy. This study elucidated the role of NFB in bridging hypoxia with CSC-related chemoresistance. It also investigated the fundamental anticancer mechanisms of DS. The results derived from this study indicate that further study may be able to translate DS into cancer therapeutics in the future.
DescriptionA thesis presented for the degree of Doctor of Philosophy Research Institute in Healthcare Science Faculty of Science and Engineering University of Wolverhampton
Series/Report no.Cat 001