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Title: Assessing efficacy and molecular mechanisms of curcumin in targeting cancer stem-like cells in colorectal cancer
Author: Karmokar, Ankur
ISNI:       0000 0004 5350 9775
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2015
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Curcumin inhibits the proliferation of chemotherapy-resistant cancer stem-like cells in cell lines but whether this contributes to its chemopreventive activity is unknown. This study aims to determine whether curcumin modulates the growth and expansion of colorectal stem-like cells in primary adenoma and carcinoma tissues, and in vivo using a patient-derived xenograft, then to elucidate a possible mechanism of action. Colorectal tissue obtained post-operatively (normal n=32, adenoma n=6, carcinoma n=40) was FACS profiled for markers of stem-like cells, aldehyde dehydrogenase (ALDH) activity and CD133 expression. The percentage of cells with ALDH[superscript high] activity was 11.8±1.8, 4.6±0.7 and 2.8±0.4 in adenoma, normal and carcinoma tissues, respectively. Equivalent values for CD133 expression were 1.2±0.6, 0.5±0.2 and 7.7±1.8%. To assess in vitro activity, single cells from adenomas and carcinomas (three patients each, in triplicate) were cultured as spheroids with clinically achievable curcumin concentrations. Curcumin significantly reduced adenoma and carcinoma sphere number, compared to controls for all patient samples, with a U-shaped dose-response in >50% of cases. Sphere size was also impaired at concentrations >1μM. Curcumin (0.2%) consumption in NOD/SCID mice injected (s.c) with cancer stem-like cells was associated with significant delay in time to palpable tumours, increased survival and reduced rate of tumour growth. There was also a ~60% reduction in proportion of ALDH[superscript high] cells in tumours from curcumin treated mice compared to controls (p<0.05). Curcumin (0.1, 1μM) treatment of Caco2 cells caused a significant decrease (p<0.01) in Nanog expression, an embryonic stem cell transcription factor, in cancer stem-like cells specifically. A protein pull-down assay confirmed the interaction between curcumin and Nanog. Curcumin reduced (p<0.01) Nanog phosphorylation in cancer stem-like cells which may destabilise the protein, leading to reduced levels. These results indicate that clinically achievable concentrations of curcumin target stem-like cells in colorectal adenomas and carcinomas, which may contribute to anti-cancer efficacy in humans.
Supervisor: Brown, Karen; Steward, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available