Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo.
OBJECTIVE
Vitamin E succinate (alpha-TOS) inhibits the growth of cancer cells without unacceptable side effects. Therefore, the mechanisms associated with the anticancer action of alpha-TOS, including ceramide-mediated apoptosis, were investigated using head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.


METHODS
Five different human HNSCC cell lines (JHU-011, JHU-013, JHU-019, JHU-022, and JHU-029) were treated with alpha-TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated. The anticancer effect of alpha-TOS was also examined on JHU-022 solid tumor xenograft growth in immunodeficient mice.


RESULTS
Alpha-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 alpha-TOS than the other cell lines. Cellular levels of ceramide, sphingomyelinase activity, caspase-3, and p53 were elevated with increasing time of exposure to alpha-TOS. The degradation of poly(ADP-ribose) polymerase protein in JHU-022 cells treated with alpha-TOS provided evidence for apoptosis. The amounts of nuclear factor kappaB, Bcl-2, and Bcl-X(L) proteins were reduced in the cells treated with alpha-TOS for 6 hours. The levels of caspase-9, murine double minute-2, and IkappaB-alpha proteins were unchanged after alpha-TOS treatment. I.p. administration of alpha-TOS slowed tumor growth in immunodeficient mice.


CONCLUSIONS
Alpha-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 alpha-TOS suggests that ceramide-mediated apoptosis may expand therapeutic strategies in the treatment of carcinoma.
Gu
Xinbin
X
Department of Oral Diagnostic Service, Howard University, Washington, District of Columbia 20059, USA. xgu@howard.edu
Song
Xiaodong
X
Dong
Yongheng
Y
Cai
Hui
H
Walters
Eric
E
Zhang
Renshu
R
Pang
Xiaowu
X
Xie
Tianpei
T
Guo
Yinhan
Y
Sridhar
Rajagopalan
R
Califano
Joseph A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D024505:Tocopherols; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002518:Ceramides; D014810:Vitamin E; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9; D024505:Tocopherols