Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells

Cho,Kyongshin; Mabasa,Lawrence; Walters,Mark  W.; Park,Chung  S.

doi:10.3892/or.2013.2404

Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells

Authors:
- Kyongshin Cho
- Lawrence Mabasa
- Mark W. Walters
- Chung S. Park
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Affiliations: Department of Animal Sciences, North Dakota State University, Fargo, ND 58102, USA
Published online on: April 12, 2013 https://doi.org/10.3892/or.2013.2404
Pages: 2237-2242

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Abstract

Increasing evidence indicates that dietary intake of methyl nutrients is associated with the risk of breast cancer. Lipotropes are methyl group-containing essential nutrients (methionine, choline, folate and vitamin B12) which play key roles in one-carbon metabolism; however, little is known about the implications of lipotropes in possible tumor-suppressive effects with chemotherapeutic drugs for breast cancer. In the present study, we investigated the in vitro effects of lipotropes on cell growth and apoptosis of MCF-7 human breast cancer cells. Cells were cultured and treated with lipotropes, and cell proliferation, apoptosis and gene expression were determined. Also, the possible synergistic effects of lipotropes with anticancer drugs, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and doxorubicin (DOX), were examined. Lipotropes significantly reduced the growth of MCF-7 cells and increased apoptosis as well as upregulation of caspase-3 and tumor protein 53 (p53) enzyme activities. Gene transcription, as measured by quantitative real-time PCR, revealed a significant increase of p53 mRNA in MCF-7 cells treated with lipotropes, but there were no differences in two drug-resistant related genes. Moreover, lipotropes showed significant additive effects with SAHA and DOX on cell growth inhibition. These results suggest that lipotropes induce apoptosis, inhibit cell growth, and display anti-proliferative effects with SAHA and DOX in MCF-7 cells. Owing to the tumor-suppressive effects observed, lipotropes in combination with chemotherapeutic drugs may be tested further in animal models as potential therapeutic agents for reducing breast cancer risk.

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1	Cho K, Mabasa L, Bae S, Walters MW and Park CS: Maternal high methyl diet suppresses mammary carcinogenesis in female rat offspring. Carcinogenesis. 33:1106–1112. 2012. View Article : Google Scholar : PubMed/NCBI
2	Zeisel SH: Epigenetic mechanisms for nutrition determinants of later health outcomes. Am J Clin Nutr. 89:1488S–1493S. 2009. View Article : Google Scholar : PubMed/NCBI
3	Van den Veyver IB: Genetic effects of methylation diets. Annu Rev Nutr. 22:255–282. 2002.PubMed/NCBI
4	Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA and Hankinson SE: Plasma folate, vitamin B₆, vitamin B₁₂, homocysteine, and risk of breast cancer. J Natl Cancer Inst. 95:373–380. 2003.PubMed/NCBI
5	Beilby J, Ingram D, Hähnel R and Rossi E: Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer. 40:1250–1254. 2004. View Article : Google Scholar : PubMed/NCBI
6	Park CS, Cho K, Bae DR, Joo NE, Kim HH, Mabasa L and Fowler AW: Methyl-donor nutrients inhibit breast cancer cell growth. In Vitro Cell Dev Biol Anim. 44:268–272. 2008. View Article : Google Scholar : PubMed/NCBI
7	Newberne PM: Lipotropic factors and oncogenesis. Adv Exp Med Biol. 206:223–251. 1986.PubMed/NCBI
8	Mason JB: Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr. 133:941S–947S. 2003.PubMed/NCBI
9	Call JA, Eckhardt SG and Camidge DR: Targeted manipulation of apoptosis in cancer treatment. Lancet Oncol. 9:1002–1011. 2008. View Article : Google Scholar : PubMed/NCBI
10	Riedl SJ and Shi Y: Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 5:897–907. 2004. View Article : Google Scholar : PubMed/NCBI
11	Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ and Pavletich NP: Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 274:948–953. 1996. View Article : Google Scholar : PubMed/NCBI
12	Eischen CM and Lozano G: p53 and MDM2: antagonists or partners in crime? Cancer Cell. 15:161–162. 2009. View Article : Google Scholar : PubMed/NCBI
13	Marks PA, Richon VM, Miller T and Kelly WK: Histone deacetylase inhibitors. Adv Cancer Res. 91:137–168. 2004. View Article : Google Scholar : PubMed/NCBI
14	Linn SC, Pinedo HM, van Ark-Otte J, van der Valk P, Hoekman K, Honkoop AH, Vermorken JB and Giaccone G: Expression of drug resistance proteins in breast cancer, in relation to chemotherapy. Int J Cancer. 71:787–795. 1997. View Article : Google Scholar : PubMed/NCBI
15	Eliopoulos AG, Kerr DJ, Herod J, Hodgkins L, Krajewski S, Reed JC and Young LS: The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene. 11:1217–1228. 1995.PubMed/NCBI
16	Cho K, Mabasa L, Fowler AW, Walsh DM and Park CS: Canola oil inhibits breast cancer cell growth in cultures and in vivo and acts synergistically with chemotherapeutic drugs. Lipids. 45:777–784. 2010. View Article : Google Scholar : PubMed/NCBI
17	Singal PK and Iliskovic N: Doxorubicin-induced cardiomyopathy. N Engl J Med. 13:900–905. 1998. View Article : Google Scholar : PubMed/NCBI
18	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
19	Feuer EJ, Wun LM, Boring CC, Flanders WD, Timmel MJ and Tong T: The lifetime risk of developing breast cancer. J Natl Cancer Inst. 85:892–897. 1993. View Article : Google Scholar : PubMed/NCBI
20	Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD and Wong LY: Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA. 285:2981–2986. 2001. View Article : Google Scholar : PubMed/NCBI
21	Das PM and Singal R: DNA methylation and cancer. J Clin Oncol. 22:4632–4642. 2004. View Article : Google Scholar : PubMed/NCBI
22	Khan N, Adhami VM and Mukhtar H: Apoptosis by dietary agents for prevention and treatment of cancer. Biochem Pharmacol. 76:1333–1339. 2008. View Article : Google Scholar : PubMed/NCBI
23	Oren M: Decision making by p53: life, death and cancer. Cell Death Differ. 10:431–442. 2003. View Article : Google Scholar : PubMed/NCBI
24	Meek DW: Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer. 9:714–723. 2009.PubMed/NCBI
25	Lapidus RG, Nass SJ and Davidson NE: The loss of estrogen and progesterone receptor gene expression in human breast cancer. J Mammary Gland Biol Neoplasia. 3:85–94. 1998. View Article : Google Scholar : PubMed/NCBI
26	Pohl A, Devaux PF and Herrmann A: Function of prokaryotic and eukaryotic ABC proteins in lipid transport. Biochim Biophys Acta. 1733:29–52. 2005. View Article : Google Scholar : PubMed/NCBI
27	Kaminski WE, Piehler A and Wenzel JJ: ABC A-subfamily transporters: structure, function and disease. Biochim Biophys Acta. 1762:510–524. 2006. View Article : Google Scholar : PubMed/NCBI
28	Park S, Shimizu C, Shimoyama T, Takeda M, Ando M, Kohno T, Katsumata N, Kang Y, Nishio K and Fujiwara Y: Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat. 99:9–17. 2006. View Article : Google Scholar : PubMed/NCBI
29	Razin A: CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J. 17:4905–4908. 1998. View Article : Google Scholar : PubMed/NCBI
30	Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP and Kouzarides T: The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem. 278:4035–4040. 2003. View Article : Google Scholar : PubMed/NCBI
31	Müller HM, Fiegl H, Goebel G, Hubalek MM, Widschwendter A, Müller-Holzner E, Marth C and Widschwendter M: MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. Br J Cancer. 89:1934–1939. 2003.PubMed/NCBI