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IDENTIFICATION OF EFFECTIVE DRUGS OR DRUG COMBINATIONS TARGETING NON – STEM BREAST CANCER CELLS AND BREAST CANCER STEM CELLS

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dc.contributor.authorHII LING WEI
dc.date.accessioned2023-10-06T15:26:15Z
dc.date.available2023-10-06T15:26:15Z
dc.date.issued2016
dc.description.abstractBreast cancer stem cells (BCSCs), as a subset of cancer cells with enriched capacity to generate breast tumors, have recently been attributed to driving cancer recurrence and metastasis. Although the importance of developing strategies to target BCSCs has been highlighted, it is conceivable that the depletion of BCSCs within a breast tumor would not lead to complete regression since non-BCSCs might still be capable of sustaining tumor growth or regaining BCSC potential. As either of these possibilities would confound the effectiveness of therapeutic agents that exclusively target BCSCs, this study aimed to develop combinatory therapeutics that apply agents targeting both BCSCs and non-BCSCs. By utilising parental cells and mammospheres as screening platforms, a total of 193 candidate molecules were identified as potent hit compounds inhibiting both BCSCs and non-BCSCs. Subsequent analysis suggested histone deacetylase (HDAC) inhibitors as a class of anti-cancer agents targeting both BCSCs and non-BCSCs. When combined with conventional chemotherapeutics, HDAC inhibitors were found to synergise DNA-damaging chemotherapeutics, namely doxorubicin and cisplatin, against BCSCs and non-BCSCs derived from MDA-MB- 468; whereas their combined treatment with anti-mitotic chemotherapy, namely paclitaxel, only exerted synergy in MDA-MB-468 non-BCSCs. Intriguingly, neither pan-HDAC, hydroxamate-based inhibitor nor class I specific, benzamide-based HDAC inhibitor was superior to be combined with conventional chemotherapeutics against these BCSCs and non-BCSCs. Further evaluations indicated that quisinostat, as the most potent HDAC inhibitor tested, managed to enhance the doxorubicininduced cytotoxicity in both BCSCs and non-BCSCs derived from different subtypes, including basal-like triple negative breast cancer (TNBC) subtypes (MDA-MB-468 and HCC38), mesenchymal-like TNBC (MDA-MB-231), and luminal-like breast cancer (MCF-7). Conversely, the synergism between quisinostat and cisplatin was TNBC subtype-dependent. Also, it was observed that both BCSCs and non-BCSCs of TNBC subtypes were more sensitive to the co-treatment of quisinostat with DNA damaging chemotherapeutics, as compared to luminal-like breast cancer subtype. Moreover, the dose reduction potentials of these combinatory regimens that revealed in this study may be exploited to reduce the dose-limited toxicities in clinical oncology. In summary, this study offered HDAC inhibitors as novel therapeutic options, either as monotherapy or combination therapy, for refractory breast cancer treatment which warrants detailed investigations.en_US
dc.identifier.urihttps://hdl.handle.net/20.500.14377/32167
dc.language.isoenen_US
dc.publisherInternational Medical Universityen_US
dc.subjectBreast Neoplasmsen_US
dc.subjectStem Cellsen_US
dc.subjectDNAen_US
dc.subjectNeoplasmsen_US
dc.titleIDENTIFICATION OF EFFECTIVE DRUGS OR DRUG COMBINATIONS TARGETING NON – STEM BREAST CANCER CELLS AND BREAST CANCER STEM CELLSen_US
dc.typeThesis
dspace.entity.typePublication
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