AbstractHSPC1 (Hsp90), a member of the anti-apoptotic Heat Shock Protein (HSP) family appears to play a pivotal role in the development and maintenance of several tumour cell characteristics and as a result has become a target for novel anti-cancer therapies. HSPC1 inhibitors have been tested in clinical trials on a wide variety of cancer types with moderate success. However, despite recent advantages in HSPC1 inhibitor development, the effects of these drugs are not consistent. A number of factors may play a role in determining cell sensitivity to these inhibitors. As Chronic Lymphocytic Leukaemia (CLL) is such a heterogeneous disease with great variation in baseline HSP levels and other proteins amongst the patient cohort, it would not be unreasonable to assume that HSPC1 inhibitors may have varying success as a treatment strategy for this disease. The present study examined the effects of four HSPC1 inhibitors on primary CLL cells, as well as cells from healthy control subjects, and analysed a number of HSPC1 client proteins to assess the efficacy of these inhibitors. Great variation in cellular response to these drugs was observed in both CLL and healthy control subjects. Analysis of HSPC1 client proteins in these cells including ZAP-70, Akt, NF-kB and HSPA1A, revealed that HSPC1 inhibitors do not effect client protein levels in all samples. The results suggest that these inhibitors should not be considered as a universal treatment strategy for CLL and provide a basis for further study into elucidating the mechanisms behind HSPC1 inhibitor resistance. The final aim of this work was to investigate the role of the microenvironment in CLL progression, where a co-culture system was used as an in-vitro tool. Whilst consistent data was obtained using cell lines, and showed that microenvironmental factors promoted resistance to HSPC1 inhibitors, use of primary CLL cells in this model produced inconsistent data, again highlighting the heterogeneity of the disease.
CitationSmith, C. M. (2015). HSPC1 inhibitors and their use in Chronic Lymphocytic Leukaemia. (Doctoral dissertation). University of Chester, United Kingdom.
PublisherUniversity of Chester
TypeThesis or dissertation
DescriptionA reference copy of this work is available at the Seaborne Library, Learning and Information Services, University of Chester, Parkgate Road, Chester, CH1 4BJ
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