Genes & Nutrition

, Volume 7, Issue 1, pp 83–89

Vitamin E succinate inhibits survivin and induces apoptosis in pancreatic cancer cells

  • Dorrelyn Patacsil
  • Sylvester Osayi
  • Anh Thu Tran
  • Francisco Saenz
  • Lydia Yimer
  • Ayesha N. Shajahan
  • Prafulla C. Gokhale
  • Mukesh Verma
  • Robert Clarke
  • Subhash C. Chauhan
  • Deepak Kumar
Research Paper

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Identifying novel chemotherapeutic and chemopreventive approaches is critical in the prevention and treatment of cancers such as pancreatic cancer. Vitamin E succinate (VES) is a redox-silent analog of the fat-soluble vitamin alpha-tocopherol. In the present study, we explored the antiproliferative action of VES and its effects on inhibitor of apoptosis proteins in pancreatic cancer cells. We show that VES inhibits cell proliferation and induces apoptosis in pancreatic cancer cells. Further, we demonstrate that VES downregulates the expression of survivin and X-linked inhibitor of apoptosis proteins. The apoptosis induced by VES was augmented by siRNA-mediated inhibition of survivin in PANC-1 cells. In summary, our results suggest that VES targets survivin signaling and induces apoptosis in pancreatic cancer cells.

Keywords

Vitamin E Vitamin E succinate Survivin Pancreatic cancer Apoptosis 

References

  1. Alleva R, Benassi MS, Pazzaglia L, Tomasetti M, Gellert N, Borghi B, Neuzil J, Picci P (2006) Alpha-tocopheryl succinate alters cell cycle distribution sensitising human osteosarcoma cells to methotrexate-induced apoptosis. Cancer Lett 232:226–235PubMedCrossRefGoogle Scholar
  2. Altieri DC (2010) Survivin and IAP proteins in cell-death mechanisms. Biochem J 430:199–205PubMedCrossRefGoogle Scholar
  3. Appel MJ, van Garderen-Hoetmer A, Woutersen RA (1996) Lack of inhibitory effects of beta-carotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters. Cancer Lett 103:157–162PubMedCrossRefGoogle Scholar
  4. Asanuma K, Moriai R, Yajima T, Yagihashi A, Yamada M, Kobayashi D, Watanabe N (2000) Survivin as a radioresistance factor in pancreatic cancer. Jpn J Cancer Res 91:1204–1209PubMedCrossRefGoogle Scholar
  5. Chawla-Sarkar M, Bae SI, Reu FJ, Jacobs BS, Lindner DJ, Borden EC (2004) Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 11:915–923PubMedCrossRefGoogle Scholar
  6. Greco E, Basso D, Fadi E, Padoan A, Fogar P, Zambon CF, Navaglia F, Bozzato D, Moz S, Pedrazzoli S, Plebani M (2010) Analogs of vitamin E epitomized by alpha-tocopheryl succinate for pancreatic cancer treatment: in vitro results induce caution for in vivo applications. Pancreas 39:662–668PubMedCrossRefGoogle Scholar
  7. Heisler T, Towfigh S, Simon N, McFadden DW (2000) Peptide YY and vitamin E inhibit hormone-sensitive and -insensitive breast cancer cells. J Surg Res 91:9–14PubMedCrossRefGoogle Scholar
  8. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  9. Kline K, Yu W, Sanders BG (2004) Vitamin E and breast cancer. J Nutr 134:3458S–3462SPubMedGoogle Scholar
  10. Kumar D, Gokhale P, Broustas C, Chakravarty D, Ahmad I, Kasid U (2004a) Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene 23:612–616PubMedCrossRefGoogle Scholar
  11. Kumar D, Sakabe I, Patel S, Zhang Y, Ahmad I, Gehan EA, Whiteside TL, Kasid U (2004b) SCC-112, a novel cell cycle-regulated molecule, exhibits reduced expression in human renal carcinomas. Gene 328:187–196PubMedCrossRefGoogle Scholar
  12. Malafa MP, Neitzel LT (2000) Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res 93:163–170PubMedCrossRefGoogle Scholar
  13. Malafa MP, Fokum FD, Andoh J, Neitzel LT, Bandyopadhyay S, Zhan R, Iiizumi M, Furuta E, Horvath E, Watabe K (2006) Vitamin E succinate suppresses prostate tumor growth by inducing apoptosis. Int J Cancer 118:2441–2447PubMedCrossRefGoogle Scholar
  14. Neuzil J (2003) Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer 89:1822–1826PubMedCrossRefGoogle Scholar
  15. Neuzil J, Wang XF, Dong LF, Low P, Ralph SJ (2006) Molecular mechanism of ‘mitocan’-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett 580:5125–5129PubMedCrossRefGoogle Scholar
  16. Ohlsson B, Albrechtsson E, Axelson J (2004) Vitamins A and D but not E and K decreased the cell number in human pancreatic cancer cell lines. Scand J Gastroenterol 39:882–885PubMedCrossRefGoogle Scholar
  17. Qian M, Sanders BG, Kline K (1996) RRR-alpha-tocopheryl succinate induces apoptosis in avian retrovirus-transformed lymphoid cells. Nutr Cancer 25:9–26PubMedCrossRefGoogle Scholar
  18. Quin J, Engle D, Litwiller A, Peralta E, Grasch A, Boley T, Hazelrigg S (2005) Vitamin E succinate decreases lung cancer tumor growth in mice. J Surg Res 127:139–143PubMedCrossRefGoogle Scholar
  19. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320PubMedGoogle Scholar
  20. Tomasetti M, Rippo MR, Alleva R, Moretti S, Andera L, Neuzil J, Procopio A (2004) Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells. Br J Cancer 90:1644–1653PubMedCrossRefGoogle Scholar
  21. Wang XF, Dong L, Zhao Y, Tomasetti M, Wu K, Neuzil J (2006) Vitamin E analogues as anticancer agents: lessons from studies with alpha-tocopheryl succinate. Mol Nutr Food Res 50:675–685PubMedCrossRefGoogle Scholar
  22. Yu W, Sanders BG, Kline K (2002) RRR-alpha-tocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-beta-independent activation of p21Waf1/Cip1. Nutr Cancer 43:227–236PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Dorrelyn Patacsil
    • 1
  • Sylvester Osayi
    • 1
  • Anh Thu Tran
    • 1
  • Francisco Saenz
    • 1
  • Lydia Yimer
    • 1
  • Ayesha N. Shajahan
    • 2
  • Prafulla C. Gokhale
    • 2
  • Mukesh Verma
    • 4
  • Robert Clarke
    • 2
  • Subhash C. Chauhan
    • 3
  • Deepak Kumar
    • 1
    • 2
  1. 1.Cancer Research Laboratory, Department of Biological and Environmental SciencesUniversity of the District of ColumbiaWashingtonUSA
  2. 2.Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  3. 3.Cancer Biology Research CenterSanford Research/University of South DakotaSioux FallsUSA
  4. 4.Methods and Technologies Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population SciencesNational Cancer InstituteBethesdaUSA

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