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The role of lysophosphatidic acid acyltransferase beta (LPAAT-β) inhibitors in acute myeloid leukaemia cell lines

Al-Bakistani, Hamed Abdul Aziz 2005. The role of lysophosphatidic acid acyltransferase beta (LPAAT-β) inhibitors in acute myeloid leukaemia cell lines. PhD Thesis, Cardiff University.

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In this study, we found CT-32228, as well as its analogues PC020702 induce potent cytotoxicity against AML cell lines. We show that, PC020702 significantly inhibited LIPAAT-β enzyme activity after 24 h of induction and insignificantly after 1 hour. Oligonucleotide array data showed an involvement G-protein coupled receptor protein signalling pathway. PC020702 triggered apoptosis in AML cells via caspase-3 and annexin V. We have focused on the potential therapeutic applications of inhibiting the production of PA, a lipid cofactor for the activation of raf and thus the Ras/Raf/MAPK pathway, for mTOR (mammalian target of rapamycin), a critical effecter molecule downstream in the phosphatidylinositol-3-kinase (PI3K) pathway. Importantly, PC020702 neither inhibited mTOR nor Erk1/2 phosphorylation. However, PC020702 inhibited Akt phosphorylation that is not known as a target for PA. Our studies have not supported the hypothesis. However, the pharmacological action of LPAAT-β inhibitors, oligonucleotide array data and Western blotting analysis, have demonstrated that the inhibitory affect of PC020702 and CT32228 were on LPA signal transduction pathways and not PA pathways. The main points that supported our hypothesis were as follows; Neither Ras/Raf/MAPK nor mTOR were inhibited that known activated directly by PA while Phospho-Akt was inhibited that not known as PA target. PA may produce by other enzymes mainly PLD and DAGK that may act other sources of PA. G-protein-coupled receptors genes activation was triggered by early induction of inhibitors as analyzed by Gene Ontology terminology. LPAAT-β inhibitors inhibit LPA which induces cytotoxicity in AML cells, providing the framework for clinical trials of these agents in AML.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 31 Jan 2020 05:53

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