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Vitamin E Succinate Induces Ceramide-Mediated Apoptosis in Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Authors' Affiliations: Departments of ¹ Oral Diagnostic Service, ² Biochemistry and Molecular Biology, and ³ Radiation Oncology, and ⁴ Cancer Center, Howard University, Washington, District of Columbia; ⁵ Shanghai TenGen Biomedical Co. Ltd., Shanghai, China; ⁶ Experiment Center, Binzhou Medical College, Shandong, China; ⁷ Oriental TenGen Tech Development Co. Ltd., Beijing, China; and ⁸ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Xinbin Gu, Department of Oral Diagnostic Service, College of Dentistry, Howard University, 600 W Street, NW, Washington, DC 20059. Phone: 202-806-0345; Fax: 202-806-0446. E-mail: xgu{at}howard.edu.

Purpose: Vitamin E succinate (-TOS) inhibits the growth of cancer cells without unacceptable side effects. Therefore, the mechanisms associated with the anticancer action of -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 -TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated. The anticancer effect of -TOS was also examined on JHU-022 solid tumor xenograft growth in immunodeficient mice.

Results: -TOS inhibited the growth of all the HNSCC cell lines in vitro in a dose- and time-dependent manner. Thus, JHU-013 and JHU-022 cell lines were more sensitive to -TOS than the other cell lines. Cellular levels of ceramide, sphingomyelinase activity, caspase-3, and p53 were elevated with increasing time of exposure to -TOS. The degradation of poly(ADP-ribose) polymerase protein in JHU-022 cells treated with -TOS provided evidence for apoptosis. The amounts of nuclear factor B, Bcl-2, and Bcl-X_L proteins were reduced in the cells treated with -TOS for 6 hours. The levels of caspase-9, murine double minute-2, and IB- proteins were unchanged after -TOS treatment. I.p. administration of -TOS slowed tumor growth in immunodeficient mice.

Conclusions: -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 -TOS suggests that ceramide-mediated apoptosis may expand therapeutic strategies in the treatment of carcinoma.