Abstract

A Combination of Redeployed Drugs Demonstra Potent Anti-leukaemia and Anti-lymphoma Activity through Disruption of Tumour Cell de Novo Lipogenesis

Andrew Southam, PostDoc Fellow, University of Birmingham

Cancer cells exhibit elevated fatty acid biosynthesis which is important for tumour cell proliferation and survival, and which is now accepted to be one of the hallmarks of cancer [1,2]. We have previously demonstrated that combined Bezafibrate and medroxyProgesterone acetate therapy (denoted BaP) kills leukaemia and lymphoma cells, and is non-toxic to non-tumour cells, both in vitro and in vivo in phase II clinical trials[3-5]. Here, mass spectrometry lipidomics was utilised to investigate the action of BaP on the lipidome and de novo lipogenesis in acute myeloid leukemia (AML) and Burkitts lymphoma (BL) cell lines. Within 24hrs, BaP significantly decreased phospholipid synthesis from 13C-glucose, considerably altering phospholipid acyl chain composition. Western blot analysis demonstrated that BaP altered key lipogenic enzymes including decreasing stearoyl-CoA desaturase-1 (SCD-1) protein levels and increasing inhibitory phosphorylation of acetyl-CoA carboxylase (ACC). Both AML and BL cells were rescued from BaP killing by the addition of exogenous oleic acid, but not palmitic acid. To conclude, we demonstrate that BaP inhibition of lipogenesis in leukaemia and lymphoma cells is an important component of the anti-cancer activity of BaP and is mediated by alteration of keys enzymes in fatty acid synthesis.