期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 95, 期 -, 页码 190-199出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.03.018
关键词
Cancer; Sphingolipid; Vitamin E metabolites; Autophagy; Apoptosis
资金
- National Institutes of Health [R21CA152588, R01AT006882]
- NIH via Purdue Center for Cancer Research [P30CA023168]
Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied delta T-13'-COOH and delta TE-13'-COOH, which are metabolites of delta-tocopherol and delta-tocotrienol, respectively. delta TE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and delta-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, delta TE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents. (C) 2016 Elsevier Inc. All rights reserved.
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