Examining the role of novel lignan compounds as anti-leukaemia agents

Wainwright, Thomas (2018) Examining the role of novel lignan compounds as anti-leukaemia agents. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

Leukaemia is a family of haematological malignancies and is responsible for approximately 4500 deaths in the UK annually. Despite extensive research and development within this disease area over the last decade, there has been little change in the overall survival, risk of relapse and side effects, highlighting the need for improved chemotherapeutics. Lignans are polyphenolic compounds found naturally in plants and have been suggested to have antioxidant properties and inhibitory effects on the Wnt/ß-catenin and the PI3K/Akt cell signalling pathways which are aberrantly activated in leukaemia. A series of eighteen novel compounds have been synthesised based on a natural lignan extract, each with structural modifications to the side chains of each molecule. The effects of the eighteen lignan derivatives on the leukaemia cell line Jurkat were investigated. Biochemical activity as an indirect measure of viability was assessed using the MTS assay, while apoptosis and necrosis were investigated using the Annexin V/Propidium Iodide assay. Cell cycle analysis by DNA quantification was also performed to determine any arrest in cycle induced by the compounds. Additionally, Western Blotting analysis was performed on lignan treated cell lysates to identify changes in protein expression that would suggest effects on the Wnt/ß-catenin and the PI3K/Akt signalling pathways. HSPB1 and HSPA1A expression was analysed to determine the cellular stress response. Data indicate that the lignan compounds SD007, SD013 and SD018 significantly affect cellular metabolism and induce apoptosis following treatment. Cell cycle analysis demonstrates there is a significant reduction in Jurkat cells entering G2- phase, which further indicates the pro-apoptotic effect of the lignan compounds. Western Blotting analysis suggests there is a cellular stress response induced by lignan compound treatment, due to the increased expression of the stress protein HSPB1. However, no change in phosphorylated levels of ß-catenin or Akt were observed, suggesting that these particular lignan compounds have no effect on the Wnt/ß-catenin or the PI3K/Akt pathways. Further study is necessary to establish the cell signalling cascades affected by lignan compound treatment, however the data obtained highlight lignan compounds SD007, SD013 and SD018 for further development and refinement as anti-leukaemia agents.