DOI QR코드

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Effects of $\alpha$-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells

  • Na, Mi-Hee ;
  • Seo, Eun-Young ;
  • Kim, Woo-Kyoung
  • Published : 2009.12.31

Abstract

The role that antioxidants play in the process of carcinogenesis has recently gained considerable attention. $\alpha$-Lipoic acid, a naturally occurring disulfide molecule, is a powerful antioxidant that reportedly exerts beneficial effects in patients with advanced cancer by reducing the level of reactive oxygen species and increasing glutathione peroxidase activity. In this study, we examined changes in the protein and mRNA expression associated with cell proliferation and apoptosis in MDA-MB-231 breast cancer cultured in the presence of various concentrations (0, 250, 500, and 1000 ${\mu}mol/L$) of $\alpha$-lipoic acid. The results revealed that $\alpha$-lipoic acid inhibited the growth of breast cancer cells in a dose-independent manner (P < 0.05). Additionally, $ErbB_2$ and $ErbB_3$ protein and mRNA expressions were significantly decreased in a dose-dependent manner in response to $\alpha$-lipoic acid (P < 0.05). Furthermore, the protein expression of phosphorylated Akt (p-Akt) levels and total Akt, and the mRNA expression of Akt were decreased dose-dependently in cells that were treated with $\alpha$-lipoic acid (P < 0.05). Bcl-2 protein and mRNA expressions were also decreased in cells that were treated with $\alpha$-lipoic acid (P < 0.05). However, Bax protein and mRNA expressions were increased in cells treated with $\alpha$-lipoic acid (P < 0.05). Finally, caspase-3 activity was significantly increased in a dose-dependent manner in cells treated with $\alpha$-lipoic acid (P < 0.05). In conclusion, we demonstrated that $\alpha$-lipoic acid inhibits cell proliferation and induces apoptosis in MDA-MB-231 breast cancer cell lines.

Keywords

$\alpha$-Lipoic acid;proliferation;apoptosis;breast cancer;MDA-MB-231 cells

References

  1. Gurer H, Ozgunes H, Oztezcan S & Ercal N (1999). Antioxidant role of alpha-lipoic acid in lead toxicity. Free Radic Biol Med 27:75-81 https://doi.org/10.1016/S0891-5849(99)00036-2
  2. Olayioye MA, Neve RM, Lane HA & Hynes NE (2000). The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159-3167 https://doi.org/10.1093/emboj/19.13.3159
  3. Perez-Nadales E & Lloyd AC (2004). Essential function for ErbB3 in breast cancer proliferation. Breast Cancer Res 6:137-139 https://doi.org/10.1186/bcr792
  4. Vig-Varga E, Benson EA, Limbil TL, Allison BM, Geobl MG & Harrington MA (2006). Alpha-lipoic acid modulate ovarian surface epithelial cell growth. Gynecol Oncol 103:45-52 https://doi.org/10.1016/j.ygyno.2006.01.060
  5. Larghero P, Vene R, Minghelli S, Travaini G, Morini M, Ferrari N, Pfeffer U, Noonan DM, Albini A & Benelli R (2007). Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression. Carcinogenesis 28:1008-1020 https://doi.org/10.1093/carcin/bgl233
  6. Reed LJ, Debusk BG, Cunsalus IC & Hornberger CS Jr (1951). Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase. Science 27:93-94 https://doi.org/10.1126/science.114.2952.93
  7. Simbula G, Columbano A, Ledda-Columbano GM, Sanna L, Deidda M, Diana A & Pibiri M (2007). Increased ROS generation and p53 activation in alpha-lipoic acid -induced apoptosis of hepatoma cells. Apoptosis 12:113-123 https://doi.org/10.1007/s10495-006-0487-9
  8. Alnemri ES (1997). Mammalian cell death proteases: a family of highly conserved aspartate specific cysteine proteases. J Cell Biochem 64:33-42 https://doi.org/10.1002/(SICI)1097-4644(199701)64:1<33::AID-JCB6>3.0.CO;2-0
  9. Pack RA, Hardy K, Madigan MC & Hunt NH (2002). Differential effects of the antioxidant alpha-lipoic acid on the proliferation of mitogenstimulated peripheral blood lymphocytes and leukemic T cell. Mol Immunol 38:733-745 https://doi.org/10.1016/S0161-5890(01)00110-9
  10. Palacios J, Robles-Frias MJ, Castilla MA, Lopez-Garcia MA & Benitez J (2008). The molecular pathology of hereditary breast cancer. Pathobiology 75:85-94 https://doi.org/10.1159/000123846
  11. Cameron NE, Coteer MA, Horrobin DH & Tritschler HJ (1998). Effects of alpha-lipoic acid on neurovascular function in diabetic rats: interation with essential fatty acids. Diabetologia 41:390-399 https://doi.org/10.1007/s001250050921
  12. Ministry of Health and Welfare and Family (2008). Annual report of National Cancer Registration. https://u-lib.nanet.go.kr/dl/Simple View.php. Accessed on 8/14/2009
  13. Moungjaroen J, Nimmannit U, Callery PS, Wang L, Azad N, Lipipun V, Chanvorachote P & Rojanasakul Y (2006). Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid on human lung epithelial cancer cell through Bcl-2 down regulation. J Pharmacol Exp Ther 319:1062-1069 https://doi.org/10.1124/jpet.106.110965
  14. Jeoung SY (2006). The effect of lipoic acid on antioxidant enzyme system in murine melanoma cells. Master thesis, SookMyung University, Seoul. Republic of Korea
  15. Seo EY & Kim WK (2006). Effect of [6]-gingerol on bcle-2 and Bax expression in MDA-MB-231 human breast cancer cell line. Journal of the Korean Society of Food Science and Nutrition 35:671-676 https://doi.org/10.3746/jkfn.2006.35.6.671
  16. Lee HS, Seo EY & Kim WK (2004). Resveratrol induces apoptosis in SW480 human colon cancer cell lines. Food Sci Biotechnol 13:80-84
  17. Kang HJ, Kim SW, Yun YK, Oh SK, Choe KJ & Noh DY (2001). Expression of p53, c-erbB2, bcl-2, Cathepsin D in lnfiltrating Ductal Cancer of the Breast. Jornal of the Korean Surgical Society 60:592-599
  18. Wenzel U, Nickel A & Daniel H (2005). alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-$\ast$- generation. Apoptosis 10:359-368 https://doi.org/10.1007/s10495-005-0810-x
  19. Huang WY, Newman B, Milliken RC, Conway K, Hulka BS, Schell MJ & Liu ET (2000). Risk of breast cancer according to the status of HER-2/neu oncogene amplification. Cancer Epidemiol Biomarkers Prev 9:65-71
  20. Sen CK, Sashwati R & Packer L (1999). Fas mediated apoptosis of human Jurkat T-cells: intracellular events and potentiation by redox-active alpha-lipoic acid. Cell Death Differ 6:481-491 https://doi.org/10.1038/sj.cdd.4400514
  21. Bianco R, Gelardi T, Damiano V, Ciardiello F & Tortora G (2007). Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol 39:1416-1431 https://doi.org/10.1016/j.biocel.2007.05.008
  22. Hortbagyi GN, de la Garza Salazar J, Pritchard K, Amodori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O'Shaughnessy JA, Shen ZZ & Albain KS (2005). The global breast cancer burden:variation in epidemiology and survival. Clin Breast Cancer 6:391-401 https://doi.org/10.3816/CBC.2005.n.043
  23. Xue C, Liang F, Mahmood R, Vuolo M, Wyckoff J, Qian H, Tsai KL, Kim MM, Locker J, Zhang ZY & Segall JE (2006). ErbB3-Dependent Motility and Intravasation in Breast Cancer Metastasis. Cancer Res 66:1418-1426 https://doi.org/10.1158/0008-5472.CAN-05-0550
  24. Packer L (1998). alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev 30:245-275 https://doi.org/10.3109/03602539808996311
  25. Marsh SA, Laursen PB, Pat BK, Gobe GC & Coombes JS (2005). Bcl-2 in endothelial cells is increased by vitamin E and alpha-lipoic acid supplementation but not exercise training. J Mol Cell Cardiol 38:445-451 https://doi.org/10.1016/j.yjmcc.2004.11.026
  26. Zhai H, Chen X & Hu Z (2003). Study on the relationship between intake of trace elements and breast cancer mortality with chemometric methods. Comput Biol Chem 27:581-586 https://doi.org/10.1016/S1476-9271(03)00049-5
  27. Guy PM, Platko JV, Cantley LC, Cerione RA & Carraway KL (1994). Insect cell-expressed $p180^{erbB3}$ possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci U S A 91:8132-8136 https://doi.org/10.1073/pnas.91.17.8132
  28. Kim WK, Bang MH, Kim ES, Kang NE, Jung KC, Cho HJ & Park JHY (2005). Quercetin decreases the expression of $ErB_{2}$ and $ErB_{3}$ proteins in HT-29 human colon cancer cells. J Nutr Biochem 16:155-162 https://doi.org/10.1016/j.jnutbio.2004.10.010
  29. Riese DJ & Stern DF (1998). Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 20:41-48 https://doi.org/10.1002/(SICI)1521-1878(199801)20:1<41::AID-BIES7>3.0.CO;2-V

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