title: 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 = 1.7 × 10(-4)). 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.
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom. A.D.Southam@bham.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Southam
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Farhat L
authors.initials: FL
authors.lastname: Khanim
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Hayden
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Constantinou
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Koczula
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Michell
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Viant
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bunce
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001629:Bezafibrate / Q000008:administration & dosage; D045744:Cell Line, Tumor; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D011379:Prognosis; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D017258:Medroxyprogesterone Acetate; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D001629:Bezafibrate