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

Abstract

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...

Oral-Specific Chemical Carcinogenesis in Mice: An Exciting Model for Cancer Prevention and Therapy

“…Liposomal curcumin suppresses HNSCC growth in vitro and in vivo via an AKT-independent pathway (29). Vitamin E succinate also inhibits HNSCC growth and viability in vivo and in vitro (30). Testing these agents alone and in combinations (possibly including mTOR inhibitors) in the oral-specific mouse model would be a logical step in evaluating their potential for oral cancer prevention.…”

Gene alterations in head and neck carcinomas and their role in promoting malignant behavior (Review)

“…In HNSCC, Gu et al showed promising anticancer effects of vitamin E succinate to inhibit HNSCC growth and viability via ceramide-mediated apoptosis. This was found in both cancer cells and in a xenograft cancer mouse model (89). Other groups have attempted to find ways to deliver ceramide into HNSCC cells successfully (90).…”

-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis

“…At present, the mechanism underlying the effect of VES and TS-1 on activating PP2A phosphatase activity remains unclear. We hypothesize that this PP2A activation might be attributed to increased intracellular levels of ceramide, a known PP2A activator, in drugtreated cells since VES has been reported to stimulate ceramide production (13,23). The ability of VES and TS-1 to mediate ceramideinduced PP2A activation is currently under investigation.…”

“…Substantial evidence indicates that VES exhibits a unique ability to target multiple signaling pathways associated with carcinogenesis, tumor progression and metastasis , including those mediated by nuclear factor kappaB (17,24), protein kinase Ca (25), sphingolipids (13,23), Bcl-2/Bcl-xL (16), androgen receptor (AR) (10), vascular endothelial growth factor (7) and insulin-like growth factor-binding protein-3 (22). Although some of these signaling targets might be cancer type specific, this broad spectrum of action in conjunction of low toxicity underlies the therapeutic value of developing VES into useful agents for cancer treatment or prevention.…”