Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids

Abstract

The redeployed drug combination of bezafibrate and medroxyprogesterone acetate (designated BaP) has potent in vivo anticancer activity in acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) patients; however, its mechanism-of-action is unclear. Given that elevated fatty acid biosynthesis is a hallmark of many cancers and that these drugs can affect lipid metabolism, we hypothesized that BaP exerts anticancer effects by disrupting lipogenesis. We applied mass spectrometry-based lipidomics and gene and protein expression measurements of key lipogenic enzymes [acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase 1 (SCD1)] to AML and eBL cell lines treated with BaP. BaP treatment decreased fatty acid and phospholipid biosynthesis from 13 C D-glucose. The proportion of phospholipid species with saturated and monounsaturated acyl chains was also decreased after treatment, whereas those with polyunsaturated chains increased. BaP decreased SCD1 protein levels in each cell line (0.46-to 0.62-fold; P < 0.023) and decreased FASN protein levels across all cell lines (0.87-fold decrease; P ¼ 1.7 Â 10 À4 ). Changes to ACC1 protein levels were mostly insignificant. Supplementation with the SCD1 enzymatic product, oleate, rescued AML and e-BL cells from BaP cell killing and decreased levels of BaP-induced reactive oxygen species, whereas supplementation with the SCD1 substrate (and FASN product), palmitate, did not rescue cells. In conclusion, these data suggest that the critical anticancer actions of BaP are decreases in SCD1 levels and monounsaturated fatty acid synthesis. To our knowledge, this is the first time that clinically available antileukemic and antilymphoma drugs targeting SCD1 have been reported. Cancer Res; 75(12); 2530-40. Ó2015 AACR.

Probing the action of a novel anti-leukaemic drug therapy at the single cell level using modern vibrational spectroscopy techniques

“…This band would also have contributions from methyl and methylene modes from amino acid side chains of proteins but the fact that there is also a correlation with the increase in intensity of the bands in the methyl/methylene stretching region (3000–2800 cm −1 ) indicates that the major changes are the result of changes in lipids and not proteins. This is consistent with our previous mass spectrometry lipidomics study where BaP treated AML cells had more unsaturated phosphatidylcholine than control cells 8 . An explanation for this altered lipid saturation is that BaP has been shown to decrease de novo fatty acid synthesis—synthesis of saturated and monounsaturated fatty acids and increase uptake of polyunsaturated fatty acids from the media 8 .…”

“…The combination of these drugs (denoted BaP) has a potent anticancer effect on the HL60 and K562 cell lines that are used in this study 7, 8 .…”

“…The redeployed combination of the cholesterol lowering drug, bezafibrate, and the female contraceptive, medroxyprogesterone acetate (combination denoted BaP) has anti-leukaemic and anti-lymphoma activity without haematological toxicity both in vitro and in patients 4–7 . Mass spectrometry lipidomics of BaP treated AML cell lines has recently demonstrated that BaP slows de novo fatty acid biosynthesis, particularly the synthesis of monounsaturated fatty acids, which plays a key role in BaP-related AML cell killing 8 . This has relevance in the wider cancer field where tumour cells often have up-regulated fatty acid synthesis and inhibition of this process leads to tumour cell death 9, 10 .…”

“…This has relevance in the wider cancer field where tumour cells often have up-regulated fatty acid synthesis and inhibition of this process leads to tumour cell death 9, 10 . The effect of BaP on de novo lipogenesis also led to a broad change in the overall phospholipid acyl chain composition, which may play a role in cell killing 8 . A spectroscopic investigation of the action of BaP at the single cell level offers an original insight into the mode of action of this combination therapy in which living cells can be monitored with BaP treatment.…”

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

“…Therefore, assimilating exogenous lipids would replenish lipid supplies and restore leukaemia cell proliferation. Supporting this notion, increased lipid mobilization had been observed in chronic lymphocytic leukaemia (CLL) patients as the lipolysis activity is significantly enhanced4546.…”