Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Abstract

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 δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-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 5-lipoxygnease (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anti-cancer 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 dihydrosphingosin 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'-COOHinduced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-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.

Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment

“…Meanwhile, cells treated with γTE had decreased C 16:0 -SM and total SMs throughout the treatment compared with controls. Interestingly, we have recently shown that long-chain carboxychromanols (vitamin E metabolites) caused similar temporal changes of sphingolipids in cancer cells at a faster rate than γTE [28]. The time-based alteration of sphingolipids provides clues of potential cellular target(s) of γTE and the role of specific sphingolipids in γTE-mediated anticancer effects.…”

“…Sphingolipids were measured by a LC-MS/MS method modified based on previous publications [27, 28]. Analyses were performed using the Agilent 6460 triple quadrupole mass spectrometer coupled with the Agilent 1200 Rapid Resolution HPLC (Agilent Technologies, Santa Clara, CA) with detection of sphingolipids in positive mode by multiple reaction monitoring (MRM) technique.…”

Natural forms of vitamin E and metabolites—regulation of cancer cell death and underlying mechanisms

“…Specifically, αT‐13′‐COOH and δT‐13′‐COOH induced apoptosis in HepG2 human liver cancer cells, as indicated by activated caspase 3, 7 and 9, and PARP cleavage . We demonstrate that δT‐13′‐COOH and δTE‐13′‐COOH inhibit proliferation and induce apoptosis in HCT116 and HT‐29 human colon cancer cells, as indicated by PARP cleavage and caspase 9 activation . δT‐13′‐COOH and δTE‐13′‐COOH treatment also induced autophagy, as indicated by increased LC‐3II .…”

“…We demonstrate that δT‐13′‐COOH and δTE‐13′‐COOH inhibit proliferation and induce apoptosis in HCT116 and HT‐29 human colon cancer cells, as indicated by PARP cleavage and caspase 9 activation . δT‐13′‐COOH and δTE‐13′‐COOH treatment also induced autophagy, as indicated by increased LC‐3II . Interestingly, normal colon epithelial (CCD841CoN) cells appeared to be much less sensitive to δT‐13′‐COOH and δTE‐13′‐COOH treatment, suggesting selective induction of death in cancer cells .…”

“…B), which are metabolites of αT and δT , respectively, have been shown to be stronger than tocopherols in inhibition of proliferation and induction of death in human liver cancer cells . δT‐13′‐COOH and δTE‐13′‐COOH (a metabolite of δTE) suppressed the growth and induced death of human colon cancer cells, and are much stronger than γT or δT for these effects .…”