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.
Highlights
Acute myelogenous leukemia (AML) and endemic Burkitt lymphoma are two aggressive and biologically very distinct blood cancers that kill patients quickly if untreated
This is not surprising, given that the cell lines were derived from different individuals with distinct forms of AML (HL60 are de novo AML M2 cells and K562 are AML cells derived from a chronic myeloid leukemia patient undergoing blast crisis; ref. 37, 38)
Enhanced lipogenesis, arising from increased activities of fatty acid biosynthetic enzymes (including acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase (SCD1)—see the pathways map in Fig. 7), is a metabolic hallmark of many cancer cells [15,16,17]
Summary
Acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) are two aggressive and biologically very distinct blood cancers that kill patients quickly if untreated. AML mainly affects elderly patients, who often cannot tolerate routine highgrade cytotoxic chemotherapy treatment [1, 2]. EBL is a B-cell nonHodgkin lymphoma predominantly affecting children in equatorial Africa. It responds well to high-grade chemotherapy; the high costs of treatment and supportive care often preclude their use in the endemic setting [3]. In elderly AML patients in high-income countries and eBL patients in lowincome countries, there is an urgent need for inexpensive treatments that selectively kill tumor cells with low systemic toxicity. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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