Skip to main content

Advertisement

Log in

Vitamin E Derivative with Modified Side Chain Induced Apoptosis by Modulating the Cellular Lipids and Membrane Dynamics in MCF7 Cells

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

The vitamin E derivative with side chain modification (TC6OAc) has been shown to possess anticancer activity in our earlier in vivo studies. It was hypothesized that, as Vitamin E (VE) and VE derivative are fat soluble lipophilic molecules, they exert their function by modulating the lipid metabolism and related pathways. This study aimed to evaluate the cellular impact of this VE derivative (2,5,7,8-Tetramethyl-2-(4′-Methyl-3′-Pentenyl)-6-Acetoxy Chromane-TC6OH), using α-tocopherol as a reference compound throughout the experiments. Their effects on the cellular metabolism, the biophysical properties of cellular lipids and the functional characteristics of cells were monitored in human estrogen receptor (ER) positive breast cancer cells. It has been documented that TC6OH treatment induces tumor cell apoptosis by dissipating the mitochondrial membrane potential, modulating the lipid, transportation and degradation as well as downregulating certain anti-apoptotic and growth factor related proteins. Due to resistance of ER positive cells to the established therapies, the findings of this study are of translational value.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Ackerman, D., & Simon, M. C. (2014). Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends in Cell Biology, 24, 472–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cruz, P. M., Mo, H., McConathy, W. J., Sabnis, N., & Lacko, A. G. (2013). The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Frontiers in Pharmacology, 4, 119.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Baenke, F., Peck, B., Miess, H., & Schulze, A. (2013). Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Disease Models & Mechanisms, 6, 1353–1363.

    Article  CAS  Google Scholar 

  4. Dwivedi, P., Rodriguez, J., Ibe, N. U., & Weers, P. M. M. (2016). Deletion of the N- or C-terminal helix of apolipophorin III to create a four-helix bundle protein. Biochemistry, 55(26), 3607–3615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dwived, P. (2017). Apolipophorin III: a unique insect protein.EC. Microbiology, 10(5), 186–196.

    Google Scholar 

  6. Huebbe, P., Lodge, J. K., & Rimbach, G. (2010). Implications of apolipoprotein E genotype on inflammation and vitamin E status. Molecular Nutrition & Food Research, 54(5), 623–630.

    Article  CAS  Google Scholar 

  7. Ortega, H., Castilla, P., Gómez-Coronado, D., Garcés, C., Benavente, M., Rodríguez-Artalejo, F., Oya, M., & Lasunción, M. A. (2005). Influence of apolipoprotein E genotype on fat-soluble plasma antioxidants in Spanish children. The American Journal of Clinical Nutrition, 81(3), 624–632.

    Article  CAS  PubMed  Google Scholar 

  8. Yang, C. S., Suh, N., & Kong, A. N. (2012). Does vitamin E prevent or promote cancer? Cancer Prevention Research, 5, 701–705.

    Article  CAS  PubMed  Google Scholar 

  9. McIntyre BS, Briski KP, Gapor A, Sylvester PW (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine, 224, 292–301.

  10. Neuzil, J., Weber, T., Schroder, A., Lu, M., Ostermann, G., Gellert, N., Mayne, G. C., Olejnicka, B., Negre-Salvayre, A., Sticha, M., Coffey, R. J., & Weber, C. (2001a). Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. FASEB Journal 15, 403–415.

    Article  CAS  PubMed  Google Scholar 

  11. Weber, T., Lu, M., Andera, L., Lahm, H., Gellert, N., Fariss, M. W., Korinek, V., Sattler, W., Ucker, D. S., Terman, A., Schroder, A., Erl, W., Brunk, U. T., Coffey, R. J., Weber, C., & Neuzil, J. (2002). Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clinical Cancer Research, 8, 863–869.

    CAS  PubMed  Google Scholar 

  12. Sigounas, G., Anagnostou, A., & Steiner, M. (1997). dl-alphα-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells. Nutrition and Cancer, 28, 30–35.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang, Q. (2017). Natural forms of vitamin E as effective agents for cancer prevention and therapy. Advances in Nutrition, 6, 850–867.

    Article  Google Scholar 

  14. Asay, S., Graham, A., Hollingsworth, S., Barnes, B., Oblad, R. V., Michealis, D. J., & Kenealey, J. D. (2020). γ-Tocotrienol and α-tocopherol ether acetate enhance docetaxel activity in drug-resistant prostate cancer cells. Molecules, 25(2), 398.

    Article  CAS  PubMed Central  Google Scholar 

  15. Anderson, K., Lawson, K. A., Simmons-Menchaca, M., Sun, L., Sanders, B. G., & Kline, K. (2004a). Alpha-TEA plus cisplatin reduces human cisplatin-resistant ovarian cancer cell tumor burden and metastasis. Experimental Biology and Medicine, 229, 1169–1176.

    Article  CAS  PubMed  Google Scholar 

  16. Anderson, K., Simmons-Menchaca, M., Lawson, K. A., Atkinson, J., Sanders, B. G., & Kline, K. (2004b). Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E Succinate and vitamin E analogue, alpha-TEA. Cancer Research, 64, 4263–4269.

    Article  CAS  PubMed  Google Scholar 

  17. Lawson, K. A., Anderson, K., Menchaca, M., Atkinson, J., Sun, L., Knight, V., Gilbert, B. E., Conti, C., Sanders, B. G., & Kline, K. (2003). Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. Molecular Cancer Therapeutics, 2, 437–444.

    CAS  PubMed  Google Scholar 

  18. Arya, P., Alibhai, N., Qin, H., Burton, G. W., Batist, G., You, S. X., & Alaoui-Jamali, M. A. (1998). Design and synthesis of analogs of vitamin E: antiproliferative activity against human breast adenocarcinoma cells. Bioorganic & Medicinal Chemistry Letters, 8, 2433–2438.

    Article  CAS  Google Scholar 

  19. Neuzil, J., Weber, T., Terman, A., Weber, C., & Brunk, U. T. (2001b). Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role. Redox Report: Communications in Free Radical Research, 6, 143–151.

    Article  CAS  PubMed  Google Scholar 

  20. Shiau, C. W., Huang, J. W., Wang, D. S., Weng, J. R., Yang, C. C., Lin, C. H., Li, C., & Chen, C. S. (2006). Alpha-Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function. The Journal of Biological Chemistry, 281, 11819–11825.

    Article  CAS  PubMed  Google Scholar 

  21. Thompson, T. A., & Wilding, G. (2003). Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells. Molecular Cancer Therapeutics, 2, 797–803.

    CAS  PubMed  Google Scholar 

  22. Tomic-Vatic, A., Eytina, J., Chapman, J., Mahdavian, E., Neuzil, J., & Salvatore, B. A. (2005). Vitamin E amides, a new class of vitamin E analogues with enhanced proapoptotic activity. International Journal of Cancer, 117, 188–193.

    Article  CAS  PubMed  Google Scholar 

  23. Birringer, M., EyTina, J. H., Salvatore, B. A., & Neuzil, J. (2003). Vitamin E analogues as inducers of apoptosis: structure-function relation. British Journal of Cancer, 88, 1948–1955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ling, L., Ismail, M., Shang, Z., Hu, Y., & Li, B. (2020). Vitamin E-based prodrug self-delivery for nanoformulated irinotecan with synergistic antitumor therapeutics. International Journal of Pharmaceutics, 577, 119049.

    Article  CAS  PubMed  Google Scholar 

  25. Svyshchuk OA, Donchenko HV, Danevych OI, Borutska ZP, Kuzmenko IV, Kosenko MV, Kirei ZM, Klymenko KP, Borodina LO, Makovetskyi VP, Andriichuk PY (2000). Method for the obtaining of 2,5,7,8-tetramethyl-2-(4′-methyl-3′-pentenyl)-6-acetoxy chromane. Ukrainian Patent UA 21527.

  26. Schmölz, L., Birringer, M., Lorkowski, S., & Wallert, M. (2016). Complexity of vitamin E metabolism. World Journal of Biological Chemistry, 7(1), 14–43.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wallert, M., Schmölz, L., Galli, F., Birringer, M., & Lorkowski, S. (2014). Regulatory metabolites of vitamin E and their putative relevance for atherogenesis. Redox Biology, 2, 495–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Horák, D., Pustovyy, V. I., Babinskyi, A. V., Palyvoda, O. M., Chekhun, V. F., Todor, I. N., & Kuzmenko, O. I. (2017). Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma. International Journal of Nanomedicine, 12, 4257–4268.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zasońska, B. A., Pustovyy, V. I., Babinskiy, A. V., Palyvoda, O. M., Chekhun, V. F., Todor, I., Petrovský, E., Kuzmenko, O. I., & Horák, D. (2019). Combined antitumor effect of surface-modified superparamagnetic maghemite nanoparticles and a vitamin E derivative on experimental Walker-256 mammary gland carcinosarcoma. Journal of Magnetism and Magnetic Materials, 471, 381–387.

    Article  Google Scholar 

  30. Kline, K., Yu, W., & Sanders, B. G. (2004). Vitamin E and breast cancer. The Journal of Nutrition, 134, 3458s–3462s.

    Article  CAS  PubMed  Google Scholar 

  31. Don, A. S., & Hogg, P. J. (2004). Mitochondria as cancer drug targets. Trends in Molecular Medicine, 10, 372–378.

    Article  CAS  PubMed  Google Scholar 

  32. Cakmak Arslan, G., & Severcan, F. (2019). The effects of radioprotectant and potential antioxidant agent amifostine on the structure and dynamics of DPPC and DPPG liposomes. Biochimica et Biophysica Acta (BBA) - Biomembranes, 6, 1240–1251.

    Article  Google Scholar 

  33. Derenne, A., Claessens, T., Conus, C., & Goormaghtigh, E. (2013). Infrared spectroscopy of membrane lipids. In G. C. K. Roberts (Ed), Encyclopedia of biophysics (pp. 1074–1081). Berlin, Heidelberg: Springer Berlin Heidelberg.

    Chapter  Google Scholar 

  34. Cakmak, G., Miller, L. M., Zorlu, F., & Severcan, F. (2012). Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: an FTIR microspectroscopic imaging study. Archives of Biochemistry and Biophysics, 520, 67–73.

    Article  CAS  PubMed  Google Scholar 

  35. Bozkurt, O., Severcan, M., & Severcan, F. (2010). Diabetes induces compositional, structural and functional alterations on rat skeletal soleus muscle revealed by FTIR spectroscopy: a comparative study with EDL muscle. The Analyst, 135, 3110–3119.

    Article  CAS  PubMed  Google Scholar 

  36. Meng, Y., Yao, C., Xue, S., & Yang, H. (2014). Application of Fourier transform infrared (FT-IR) spectroscopy in determination of microalgal compositions. Bioresources Technology, 151, 347–354.

    Article  CAS  Google Scholar 

  37. Mayers, J. J., Flynn, K. J., & Shields, R. J. (2013). Rapid determination of bulk microalgal biochemical composition by Fourier-Transform Infrared spectroscopy. Bioresources Technology, 148, 215–220.

    Article  CAS  Google Scholar 

  38. Wagner, H., Liu, Z., Langner, U., Stehfest, K., & Wilhelm, C. (2010). The use of FTIR spectroscopy to assess quantitative changes in the biochemical composition of microalgae. Journal of Biophotonics, 3, 557–566.

    Article  CAS  PubMed  Google Scholar 

  39. Cakmak, G., Zorlu, F., Severcan, M., & Severcan, F. (2011). Screening of protective effect of amifostine on radiation-induced structural and functional variations in rat liver microsomal membranes by FT-IR spectroscopy. Analytical Chemistry, 83, 2438–2444.

    Article  CAS  PubMed  Google Scholar 

  40. Wang, X.-F., Witting, P. K., Salvatore, B. A., & Neuzil, J. (2005). Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway. Biochemical and Biophysical Research Communications, 326, 282–289.

    Article  CAS  PubMed  Google Scholar 

  41. Samudio, I., Harmancey, R., Fiegl, M., Kantarjian, H., Konopleva, M., Korchin, B., Kaluarachchi, K., Bornmann, W., Duvvuri, S., Taegtmeyer, H., & Andreeff, M. (2010). Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. The Journal of Clinical Investigation, 120, 142–156.

    Article  CAS  PubMed  Google Scholar 

  42. Ozek, N. S., Tuna, S., Erson-Bensan, A. E., & Severcan, F. (2010). Characterization of microRNA-125b expression in MCF7 breast cancer cells by ATR-FTIR spectroscopy. The Analyst, 135, 3094–3102.

    Article  PubMed  Google Scholar 

  43. Yung, H. W., Charnock-Jones, D. S., & Burton, G. J. (2011). Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner. PLoS ONE, 6, e17894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roskoski, Jr., R. (2012). ERK1/2 MAP kinases: structure, function, and regulation. Pharmacological Research, 66, 105–143.

    Article  CAS  PubMed  Google Scholar 

  45. Prochazka, L., Dong, L. F., Valis, K., Freeman, R., Ralph, S. J., Turanek, J., & Neuzil, J. (2010). alpha-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels. Apoptosis, 15, 782–794.

    Article  CAS  PubMed  Google Scholar 

  46. Minn, A. J., Rudin, C. M., Boise, L. H., & Thompson, C. B. (1995). Expression of bcl-xL can confer a multidrug resistance phenotype. Blood, 86(5), 1903–1910.

  47. Han, J., & Kaufman, R. J. (2016). The role of ER stress in lipid metabolism and lipotoxicity. Journal of Lipid Research, 57(8), 1329–1338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Malhi, H., & Gores, G. J. (2008). Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Seminars in Liver Disease, 28, 360–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rutkowski, D. T., & Kaufman, R. J. (2004). A trip to the ER: coping with stress. Trends in Cell Biology, 14, 20–28.

    Article  CAS  PubMed  Google Scholar 

  50. Ohyashiki, T., Ushiro, H., & Mohri, T. (1986). Effects of α-tocopherol on the lipid peroxidation and fluidity of porcine intestinal brush-border membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes, 858, 294–300.

    Article  CAS  Google Scholar 

  51. Severcan, F., & Cannistraro, S. (1989). Model membrane partition ESR study in the presence of alphα-tocopherol by a new spin probe. Bioscience Reports, 9, 489–495.

    Article  CAS  PubMed  Google Scholar 

  52. Bisby, R. H., & Birch, D. J. S. (1989). A time-resolved fluorescence anisotropy study of bilayer membranes containing α-tocopherol. Biochemical and Biophysical Research Communications, 158, 386–391.

    Article  CAS  PubMed  Google Scholar 

  53. Severcan, F., & Cannistraro, S. (1990). A spin label ESR and saturation transfer ESR study of alphα-tocopherol containing model membranes. Chem Phys Lipids, 53, 17–26.

    Article  CAS  PubMed  Google Scholar 

  54. Srivastava, S., Phadke, R. S., Govil, G., & Rao, C. N. R. (1983). Fluidity, permeability and antioxidant behaviour of model membranes incorporated with α-tocopherol and vitamin E acetate. Biochimica et Biophysica Acta (BBA) - Biomembranes, 734, 353–362.

    Article  CAS  Google Scholar 

  55. Wassall, S. R., Wang, L., Yang McCabe, R. C., Ehringer, W. D., & Stillwell, W. (1991). Electron spin resonance study of the interaction of alpha-tocopherol with phospholipid model membranes. Chemistry and Physics of Lipids, 60, 29–37.

    Article  CAS  PubMed  Google Scholar 

  56. Wang, X., & Quinn, P. J. (1999). Vitamin E and its function in membranes. Progress in Lipid Research, 38, 309–336.

    Article  CAS  PubMed  Google Scholar 

  57. Gago-Dominguez, M., Castelao, J. E., Pike, M. C., Sevanian, A., & Haile, R. W. (2005). Role of lipid peroxidation in the epidemiology and prevention of breast cancer. Cancer Epidemiology, Biomarkers & Prevention, 14, 2829–2839.

    Article  CAS  Google Scholar 

  58. Yamauchi, R. (2007). Addition products of α‐tocopherol with lipid‐derived free radicals. In L. Gerald (Ed.) Vitamins & hormones, Volume 76, pp 309–327. San Diego, California, USA: Acemic press is an imprint of Elsevier.

  59. Niki, E. (2014). Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence. Free Radical Biology & Medicine, 66, 3–12.

    Article  CAS  Google Scholar 

  60. Athenstaedt, K., & Daum, G. (2006). The life cycle of neutral lipids: synthesis, storage and degradation. Cellular and Molecular Life Sciences, 63, 1355–1369.

    Article  CAS  PubMed  Google Scholar 

  61. Medina, M. W., Gao, F., Naidoo, D., Rudel, L. L., Temel, R. E., McDaniel, A. L., Marshall, S. M., & Krauss, R. M. (2011). Coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake. PLoS ONE, 6, e19420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sade, A., Tuncay, S., Cimen, I., Severcan, F., & Banerjee, S. (2012). Celecoxib reduces fluidity and decreases metastatic potential of colon cancer cell lines irrespective of COX-2 expression. Bioscience Reports, 32, 35–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) (Project No. 114Z424) and the National Academy of Sciences of Ukraine for this joint research project.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Feride Severcan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gok, S., Kuzmenko, O., Babinskyi, A. et al. Vitamin E Derivative with Modified Side Chain Induced Apoptosis by Modulating the Cellular Lipids and Membrane Dynamics in MCF7 Cells. Cell Biochem Biophys 79, 271–287 (2021). https://doi.org/10.1007/s12013-020-00961-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-020-00961-y

Keywords

Navigation