Endogenous Anti-Inflammatory Very-Long-Chain Dicarboxylic Acids: Potential Chemopreventive Lipids

Abstract

In a paradigm shift, cancer research efforts are being dedicated to the discovery of chemopreventive agents. The goal of this approach is to delay or prevent the progression of augmented cell division to established cancer. Research has focused on dietary supplements, drugs, and endogenous lipids that possess anti-inflammatory properties. We undertook a lipidomics analysis of potential endogenous anti-inflammatory/anti-proliferative lipids in human plasma. We performed high-resolution mass spectrometric lipidomics analyses of plasma samples from controls and patients with colorectal, kidney, pancreatic, glioblastoma, and breast cancers. We present evidence that endogenous very-long-chain dicarboxylic acids (VLCDCA) are anti-inflammatory lipids that possess chemopreventative properties. In a family of VLCDCAs, we characterized VLCDCA 28:4, which is decreased in the plasma of patients with colorectal, kidney, and pancreatic cancers. The structure of this biomarker was validated by derivatization strategies, synthesis of the analytical standard, and tandem mass spectrometry. Our data suggest that VLCDCA 28:4 may be a useful blood biomarker for a number of cancers and that resupplying this lipid, via a prodrug for example, may offer a new anti-inflammatory therapeutic strategy for delaying or preventing the progression of cancer and other inflammatory diseases.

Keywords: anti-inflammatory; cancer; chemoprevention; very-long-chain dicarboxylic acids.

Figure 1

Upper Figure: Pilot study of plasma levels (100 μL) of VLCDCA 28:4 in controls (Con; N = 15) and patients with kidney (Kid; N = 7), breast (BR; N = 7), colorectal (CRC; N = 9), or glioblastoma multiforme (GBM; N = 12) cancers. Lower Figure: Validation study of plasma levels (100 μL) of VLCDCA 28:4 in controls (Con; N = 16) and patients with colorectal (CRC; N = 26), kidney (Kid; N = 9), or pancreatic (Pan; N = 45) cancers. R represents ratio of the peak area of endogenous VLCDCA 28:4 to the peak area of 1 nanomole of [²H₂₈]DCA 16:0. *, p < 0.01 (t-test).

Figure 2

Inhibition, by VLCDCA 28:4, of lipopolysaccharide (LPS) (1 µg/mL of media) stimulation of nitric oxide (NO) release into the medium of THP-1 monocytes incubated for 48 h. in 24 well plates. NO was measured as nitrite in the medium using the Griess colorimetric procedure⁴⁰. The 0 concentration point represents the NO production by LPS, while other points represent LPS and coincubation with VLCDCA 28:4 in ethanol. The control and LPS wells also received an equal volume of ethanol. Values are the mean values of 8 wells, with the RSD ranging from 3.8 to 10.2%.

Figure 3

Biosynthetic pathway for very-long-chain fatty acids (VLCFA), the dicarboxylic acid 20:4 (DCA 20:4), and the very-long-chain dicarboxylic acid 28:4 (VLDCA 28:4). COX, cyclooxygenase; CYP, cytochrome P450; ELOVL, elongation of very-long-chain fatty acids; FALDH, fatty aldehyde dehydrogenase.