Purpose: Vitamin E succinate (a-TOS) inhibits the growth of cancer cells without unacceptable side effects.Therefore, the mechanisms associated with the anticancer action of a-TOS, including ceramide-mediated apoptosis, were investigated using head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Experimental Design: Five different human HNSCC cell lines (JHU-011, JHU-013, JHU-019, JHU-022, and JHU-029) were treated with a-TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated. The anticancer effect of a-TOS was also examined on JHU-022 solid tumor xenograft growth in immunodeficient mice. Results: a-TOS inhibited the growth of all the HNSCC cell lines in vitro in a dose-and timedependent manner. Thus, JHU-013 and JHU-022 cell lines were more sensitive to a-TOS than the other cell lines. Cellular levels of ceramide, sphingomyelinase activity, caspase-3, and p53 were elevated with increasing time of exposure to a-TOS. The degradation of poly(ADP-ribose) polymerase protein in JHU-022 cells treated with a-TOS provided evidence for apoptosis. The amounts of nuclear factor nB, Bcl-2, and Bcl-X L proteins were reduced in the cells treated with a-TOS for 6 hours. The levels of caspase-9, murine double minute-2, and InB-a proteins were unchanged after a-TOS treatment. I.p. administration of a-TOS slowed tumor growth in immunodeficient mice. Conclusions: a-TOS showed promising anticancer effects to inhibit HNSCC growth and viability in vivo and in vitro. The induction of enzymes involved in ceramide metabolism by a-TOS suggests that ceramide-mediated apoptosis may expand therapeutic strategies in the treatment of carcinoma.Each year, f31,000 Americans are diagnosed with head and neck cancer and f7,400 die from the disease (1). Overall survival rates of head and neck cancers have only marginally improved over the last three decades (2). In addition, the incidence of oral cancer in African American men has been approximately twice higher than in Caucasian men, and the 5-year relative survival is lower for African Americans (1).Therefore, novel therapeutic and preventive approaches are warranted.Accumulating evidence suggested that an esterified derivative of RRR-a-tocopherol (a-TOH), RRR-a-tocopheryl succinate (a-TOS), is a vitamin E analogue, which inhibits tumor growth (3 -7). It induces apoptosis, inhibits tumor cell proliferation and differentiation, arrests DNA synthesis, and blocks cell cycle progression in various cancer cell lines and animal models of breast, colon, head and neck, prostate, and lung cancers (8 -18). In addition, a-TOS selectively kills tumor cells without toxic effects on normal cells and tissues (4,7,18). The parent compound of vitamin E, a-TOH, is a free radical -scavenging antioxidant, which protects polyunsaturated fats from peroxidation in human body but does not induce cancer cell apoptosis (19). In contrast to a-TOH, a-TOS is a redox-inactive molecule, which has a charged side group when i...
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