DOI QR코드

DOI QR Code

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

  • Na, Mi-Hee (Department Food Science and Nutrition, Dankook University) ;
  • Seo, Eun-Young (Department Food Science and Nutrition, Dankook University) ;
  • Kim, Woo-Kyoung (Department Food Science and Nutrition, Dankook University)
  • 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

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Jeoung SY (2006). The effect of lipoic acid on antioxidant enzyme system in murine melanoma cells. Master thesis, SookMyung University, Seoul. Republic of Korea
  9. 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
  10. 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
  11. 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
  12. Lee HS, Seo EY & Kim WK (2004). Resveratrol induces apoptosis in SW480 human colon cancer cell lines. Food Sci Biotechnol 13:80-84
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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

Cited by

  1. Chestnut extract induces apoptosis in AGS human gastric cancer cells vol.5, pp.3, 2011, https://doi.org/10.4162/nrp.2011.5.3.185
  2. Inorganic sulfur reduces the motility and invasion of MDA-MB-231 human breast cancer cells vol.5, pp.5, 2011, https://doi.org/10.4162/nrp.2011.5.5.375
  3. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo vol.13, pp.14, 2012, https://doi.org/10.4161/cbt.22003
  4. vol.16, pp.sup1, 2012, https://doi.org/10.1517/14728222.2011.640320
  5. Alfa-Lipoic Acid Controls Tumor Growth and Modulates Hepatic Redox State in Ehrlich-Ascites-Carcinoma-Bearing Mice vol.2012, pp.1537-744X, 2012, https://doi.org/10.1100/2012/509838
  6. Resveratrol inhibits the protein expression of transcription factors related adipocyte differentiation and the activity of matrix metalloproteinase in mouse fibroblast 3T3-L1 preadipocytes vol.6, pp.6, 2012, https://doi.org/10.4162/nrp.2012.6.6.499
  7. Peanut sprout ethanol extract inhibits the adipocyte proliferation, differentiation, and matrix metalloproteinases activities in mouse fibroblast 3T3-L1 preadipocytes vol.7, pp.3, 2013, https://doi.org/10.4162/nrp.2013.7.3.160
  8. Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to cell death vol.8, pp.1, 2015, https://doi.org/10.1186/s13048-015-0165-z
  9. The potential protective effect of α-lipoic acid against nanocopper particle–induced hepatotoxicity in male rats vol.36, pp.9, 2017, https://doi.org/10.1177/0960327116674526
  10. Network analysis of HBV- and HCV-induced hepatocellular carcinoma based on Random Forest and Monte Carlo cross-validation vol.16, pp.3, 2017, https://doi.org/10.3892/mmr.2017.6861
  11. Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions vol.19, pp.7, 2018, https://doi.org/10.3390/ijms19072050
  12. Do Anti-Oxidants Vitamin D3, Melatonin, and Alpha-Lipoic Acid Have Synergistic Effects with Temozolomide on Cultured Glioblastoma Cells? vol.5, pp.2, 2018, https://doi.org/10.3390/medicines5020058
  13. Response: Effects of α-lipoic Acid on Differentiation of Thyroid Cancer Cells vol.25, pp.3, 2010, https://doi.org/10.3803/enm.2010.25.3.246
  14. Role of obesity-associated dysfunctional adipose tissue in cancer: A molecular nutrition approach vol.1807, pp.6, 2009, https://doi.org/10.1016/j.bbabio.2010.11.004
  15. Red Ginseng Extract Reduced Metastasis of Colon Cancer Cells In Vitro and In Vivo vol.35, pp.3, 2009, https://doi.org/10.5142/jgr.2011.35.3.315
  16. Selective cytotoxicity and combined effects of camptothecin or paclitaxel with sodium-R-alpha lipoate on A549 human non-small cell lung cancer cells. vol.66, pp.3, 2009, https://doi.org/10.1080/01635581.2013.749290
  17. Insights on the Use of α-Lipoic Acid for Therapeutic Purposes vol.9, pp.8, 2019, https://doi.org/10.3390/biom9080356
  18. Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid vol.10, pp.9, 2020, https://doi.org/10.1039/c9ra10357k
  19. Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation vol.122, pp.6, 2009, https://doi.org/10.1038/s41416-020-0729-6
  20. Lipoic acid-induced oxidative stress abrogates IGF-1R maturation by inhibiting the CREB/furin axis in breast cancer cell lines vol.39, pp.17, 2020, https://doi.org/10.1038/s41388-020-1211-x
  21. An Overview of the Antioxidant Effects of Ascorbic Acid and Alpha Lipoic Acid (in Liposomal Forms) as Adjuvant in Cancer Treatment vol.9, pp.5, 2020, https://doi.org/10.3390/antiox9050359
  22. Manganese-induced neurotoxicity and the potential protective effects of lipoic acid and Spirulina platensis vol.30, pp.7, 2020, https://doi.org/10.1080/15376516.2020.1771803
  23. Evaluation of Dissolution Profiles of a Newly Developed Solid Oral Immediate-Release Formula Containing Alpha-Lipoic Acid vol.9, pp.1, 2009, https://doi.org/10.3390/pr9010176
  24. Development and In Vitro Evaluation of 2-Methoxyestradiol Loaded Polymeric Micelles for Enhancing Anticancer Activities in Prostate Cancer vol.13, pp.6, 2009, https://doi.org/10.3390/polym13060884