13′‐Carboxychromanol, a long‐chain metabolite of delta‐tocopherol, has potent anti‐cancer effects by interrupting de novo sphingolipid synthesis in human cancer cells

Natural forms of vitamin E are metabolized to long‐chain carboxychromanols and their sulfated counterparts and the carboxychromanols have been shown to have anti‐inflammatory activities. Although long‐chain carboxychromanols were recently reported to induce apoptosis in hepatocarcinoma HepG2 cells, whether these vitamin E metabolites are effective anticancer agents against other types of cancer remains to be determined. Here we showed that 13′‐carboxychromanol (13′‐COOH), a long‐chain metabolite of delta‐tocopherol (δT), inhibited the growth and induced death of human pancreatic (PANC‐1), breast (MCF‐7) and colon (HCT‐116, HT‐29) cancer cells with IC50 of 6–8 μM, which was much more potent than tocopherols and even gamma‐tocotrienol. Using liquid chromatography tandem mass spectrometry (LC‐MS‐MS), we found that 13′‐COOH induced accumulation of intracellular dihydroceramides and dihydrosphingosin, which are sphingoid bases in the de novo synthesis of sphingolipid pathway. Importantly, this alteration of sphingolipids occurred as early as after 2‐h incubation with 13′‐COOH and therefore preceded its induction of cell death. Meanwhile, an increase of ceramides was observed after 8‐h treatment when cell death became obvious. Our studies demonstrate that 13′‐COOH has more potent anti‐cancer effect than unmetabolized vitamin E forms by modulating sphingolipid metabolism in cancer cells. Grant Funding Source : R21CA152588 and R01AT006882 from National Institutes of Health