Molecular Mechanisms of Action of Polyphenols and Polyacetylenes in Leukaemia Cell Lines

ALASWAD, Hamza Abdesalam (2023). Molecular Mechanisms of Action of Polyphenols and Polyacetylenes in Leukaemia Cell Lines. Doctoral, Sheffield Hallam University.

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Abstract

Background: Leukaemia is a malignant blood disease, the treatment of which is associated with serious side-effects and resistance. Polyphenols and polyacetylenes could provide alternative therapies. They can inhibit proliferation, arrest cell cycle and induce apoptosis in leukaemia cells. However, their therapeutic mechanisms have not been fully elucidated. Methods: The effects of polyacetylene (falcarinol) and polyphenols (delphinidin, punicalagin and quercetin) on proteasome and HDAC’s activity, and molecular targets involved in apoptosis were investigated in leukaemia cell lines. The ability of polyacetylene/polyphenols to overcome resistance to chemotherapy agents was investigated by developing a doxorubicin resistant Jurkat cell line, which was used to investigate effects of combination therapies on inhibition of ATP levels, and induction of apoptosis and autophagy, and the molecular pathways involved. Finally, the impact of photoactivation of polyacetylene/polyphenols on apoptosis and autophagy was investigated. Results: Polyacetylene/polyphenols inhibited the proteosome and modulated HDAC activity in leukaemia cells. Leading to altered apoptosis gene expression. Doxorubicin resistance was associated with increased ABCB1 mRNA expression. Combination therapies of polyacetylene/polyphenols-doxorubicin resulted in additive or synergistic reduction in cell ATP levels in non-resistant Jurkat cells. Whilst in doxorubicin resistant cells polyacetylene/polyphenols treatment enhanced responses to doxorubicin. The greatest effects were seen when falcarinol or delphinidin were used in combination with doxorubicin, here there was a reduction in cell ATP levels, a modulation of apoptotic and autophagic genes in both wild type and doxorubicin resistant Jurkat cells, which increased cell death. Finally, red, and blue photoactivation of some polyacetylene/polyphenols enhanced their activity decreasing ATP levels and activation of both extrinsic and/or intrinsic apoptosis. Conclusion: Polyacetylene/polyphenols showed great therapeutic potential in leukaemia cell lines, inhibiting proteasomes, modulating HDACs and inducing autophagy and apoptosis. They also acted synergistically with doxorubicin in both wild-type and doxorubicin-resistant cells. Furthermore, their biological activity was enhanced by photoactivation.

Item Type:	Thesis (Doctoral)
Contributors:	Thesis advisor - Jordan-Mahy, Nikki (Affiliation: Sheffield Hallam University) Thesis advisor - Le Maitre, Christine [0000-0003-4489-7107] (Affiliation: Sheffield Hallam University) Thesis advisor - Mahbub, Amani
Additional Information:	Director of studies: Dr. Nicola Jordan-Mahy / Supervisors: Prof. Christine Le Maitre and Dr. Amani Mahbub "No PQ harvesting"
Research Institute, Centre or Group - Does NOT include content added after October 2018:	Sheffield Hallam Doctoral Theses
Identification Number:	https://doi.org/10.7190/shu-thesis-00615
Depositing User:	Colin Knott
Date Deposited:	11 Jun 2024 13:46
Last Modified:	12 Jun 2024 02:00
URI:	https://shura.shu.ac.uk/id/eprint/33823

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