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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts

Authors: Nipin SP, Pramod Darvin, Young Beom Yoo, Youn Hee Joung, Dong Young Kang, Don Nam Kim, Tae Sook Hwang, Sang Yoon Kim, Wan Seop Kim, Hak Kyo Lee, Byung Wook Cho, Heui Soo Kim, Kyung Do Park, Jong Hwan Park, Soung Hoon Chang, Young Mok Yang

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Combination therapy, which reduces the dosage intensity of the individual drugs while increasing their efficacy, is not a novel approach for the treatment of cancer. Methylsulfonylmethane (MSM) is an organic sulfur compound shown to act against tumor cells. Tamoxifen is a commercially available therapeutic agent for breast malignancies.

Methods

In the current study, we analyzed the combinatorial effect of MSM and tamoxifen on the suppression of ER-positive breast cancer xenograft growth and metastasis. Additionally, we also validated the molecular targets by which the drug combination regulated tumor growth and metastasis.

Results

We observed that the combination of MSM and tamoxifen regulated cell viability and migration in vitro. The intragastric administration of MSM and subcutaneous implantation of tamoxifen tablets led to tumor growth suppression and inhibition of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5b (STAT5b) pathway. Our study also assessed the regulation of signaling molecules implicated in the growth, progression, differentiation, and migration of cancer cells, such as Jak2, STAT5b, insulin-like growth factor-1Rβ, and their phosphorylation status.

Conclusions

Study results indicated that this combination therapy inhibited tumor growth and metastasis. Therefore, this drug combination may have a synergistic and powerful anticancer effect against breast cancer.
Appendix
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Literature
1.
Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer–current status and future directions. Ann Oncol. 2009;20:1913–27.CrossRefPubMed
2.
Carey KA, Lisa AC. Biology metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer. 2009;9 Suppl 2:S73–81.PubMedPubMedCentral
3.
Parkin DM, Fernández LM. Use of statistics to assess the global burden of breast cancer. Breast J. 2006;12 Suppl 1:S70–80.CrossRefPubMed
4.
Mo H, Elson CE. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr. 1999;129(4):804–13.PubMed
5.
Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, et al. Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res. 1999;5(7):1935–44.PubMed
6.
Shuai K, Liu B. Regulation of Jak–Stat signalling in the immune system. Nat Rev Immunol. 2003;3:900–11.CrossRefPubMed
7.
8.
9.
10.
Lim EJ, Hong DY, Park JH, Joung YH, Darvin P, Kim SY, et al. Methylsulfonylmethane suppresses breast cancer growth by down-regulating stat3 and stat5b pathways. PLoS One. 2012;7(4), e33361.CrossRefPubMedPubMedCentral
11.
Joung YH, Lim EJ, Lee MY, Park JH, Ye SK, Park EU, et al. Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells. Exp Mol Med. 2005;37(4):353–64.CrossRefPubMed
12.
Riedemann J, Macaulay VM. IGF-1R signalling and its inhibition. Endocr-Relat Cancer. 2006;13:S33–43.CrossRefPubMed
13.
Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11(2):155–68.PubMed
14.
Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474–81.PubMed
15.
Abukhdeir AM, Vitolo MI, Argani P, De Marzo AM, Karakas B, Konishi H, et al. Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci U S A. 2008;105(1):288–93.CrossRefPubMed
16.
Lindner DJ, Kolla V, Kalvakolanu DV, Borden EC. Tamoxifen enhances interferon-regulated gene expression in breast cancer cells. Mol Cell Biochem. 1997;167(1–2):169–77.CrossRefPubMed
17.
Morton JI, Siegel BV. Effects of oral dimethyl sulfoxide and dimethyl sulfone on murine autoimmune lymphoproliferative disease. Proc Soc Exp Biol Med. 1986;183:227–30.CrossRefPubMed
18.
Horvath K, Noker PE, Somfai-Relle S, Glávits R, Financsek I, Schauss AG. Toxicity of methylsulfonylmethane in rats. Food Chem Toxicol. 2002;40:1459–62.CrossRefPubMed
19.
Caron JM, Bannon M, Rosshirt L, Luis J, Monteagudo L, Caron JM, et al. Methyl sulfone induces loss of metastatic properties and reemergence of normal phenotype in a metastatic cloudman S-91 (M3) murine melanoma cell line. PLoS One. 2010;5(8), e11788.CrossRefPubMedPubMedCentral
20.
DiSilvestro RA, DiSilvestro DJ, DiSilvestro DJ. Methylsulfonylmethane (MSM) intake in mice produces elevated liver glutathione and partially protects against carbon tetrachloride-induced liver injury. FASEB J. 2008;22:445–8.
21.
Beilke MA, Collins-Lech C, Sohnle PG. Effects of dimethyl sulfoxide on the oxidative function of human neutrophils. J Lab Clin Med. 1987;110:91–6.PubMed
22.
Magnuson BA, Appleton J, Ames GB. Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats. J Agric Food Chem. 2007;55(3):1033–8.CrossRefPubMed
23.
Richmond VL. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sci. 1986;39(3):263–8.CrossRefPubMed
24.
Takiyama K, Konishi F, Nakashima Y, Mumamoto C, Maruyama I. Single and 13 – Week Repeated Oral Dose Toxicity of Methylsulfonylmethane in Mice. Oyo Yakuri Pharmacometrics. 2010;79(1/2):23–30.
25.
Magnuson BA, Appleton J, Ryan B, Matulka RA. Oral developmental toxicity study of methylsulfonylmethane in rats. Food Chem Toxicol. 2007;45(6):977–84.CrossRefPubMed
26.
Ebisuzaki K. Aspirin and methylsulfonylmethane (MSM): a search for common mechanisms, with implications for cancer prevention. Anticancer Res. 2003;23(1A):453–8.PubMed
27.
Caron JM, Bannon M, Rosshirt L, O’Donovan L. Methyl sulfone manifests anticancer activity in a metastatic murine breast cancer cell line and in human breast cancer tissue–part I: murine 4 T1 (66 cl-4) cell line. Chemotherapy. 2013;59(1):14–23.PubMed
28.
Caron JM, Monteagudo L, Sanders M, Bannon M, Deckers PJ. Methyl sulfone manifests anticancer activity in a metastatic murine breast cancer cell line and in human breast cancer tissue–part 2: human breast cancer tissue. Chemotherapy. 2013;59(1):24–34.PubMed
29.
Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined Hormone Agents Trialists’ Group and the European Organization for Research and Treatment of Cancer. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 2001;19(2):343–53.PubMed
30.
Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359(9324):2131–9.CrossRefPubMed
31.
Michaud LB, Jones KL, Buzdar AU. Combination endocrine therapy in the management of breast cancer. Oncologist. 2001;6(6):538–46.CrossRefPubMed
32.
Evans AH, Pancholi S, Farmer I, Thornhill A, Evans DB, Johnston SR, et al. EGFR/HER2 inhibitor AEE788 increases ER-mediated transcription in HER2/ER-positive breast cancer cells but functions synergistically with endocrine therapy. Br J Cancer. 2010;102(8):1235–43.CrossRefPubMedPubMedCentral
33.
McGown AT, Jayson G, Pettit GR, Haran MS, Ward TH, Crowther D. Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro. Br J Cancer. 1998;77(2):216–20.CrossRefPubMedPubMedCentral
34.
McCloy RA, Shelley EJ, Roberts CG, Boslem E, Biden TJ, Nicholson RI, et al. Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells. Br J Cancer. 2013;109(12):3034–41.CrossRefPubMedPubMedCentral
35.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.CrossRefPubMed
36.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.CrossRefPubMed
37.
Chia JS, Du JL, Hsu WB, Sun A, Chiang CP, Wang WB. Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid. BMC Cancer. 2010;10:175.CrossRefPubMedPubMedCentral
38.
39.
Santen RJ, Fan P, Zhang Z, Bao Y, Song RXD, Yue W. Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids. 2009;74:586–94.CrossRefPubMed
40.
Lorizio W, Wu AH, Beattie MS, Rugo H, Tchu S, Kerlikowske K, et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res Treat. 2012;132(3):1107–18.CrossRefPubMed
41.
42.
Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, et al. The combination of green tea and tamoxifen is effective against breast cancer. Carcinogenesis. 2006;27(12):2424–33.CrossRefPubMed
43.
Chuang PY, Huang C, Huang HC. The use of a combination of tamoxifen and doxorubicin synergistically to induce cell cycle arrest in BT483 cells by down-regulating CDK1, CDK2 and cyclin D expression. Journal of Pharmaceutical Technology and Drug Research. 2013;2:12.CrossRef
44.
Chang PH, Pervaiz S, Battaglino M, Matthews JL, Clark C, Day J, et al. Synergy between preactivated photofrin-II and tamoxifen in killing retrofibroma, pseudomyxoma and breast cancer cells. Eur J Cancer. 1991;27(8):1034–9.CrossRefPubMed
45.
Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–24.CrossRefPubMed
46.
Joung YH, Na YM, Yoo YB, Darvin P, Sp N, Kang DY, et al. Combination of AG490, a Jak2 inhibitor, and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway. Int J Oncol. 2014;44(3):883–95.PubMed
47.
Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80:293–9.CrossRefPubMed
48.
Rui H, Xu J, Mehta S, Fang H, Williams J, Dong F, et al. Activation of the Jak2-Stat5 Signaling Pathway in Nb2 Lymphoma Cells by an Anti-apoptotic Agent, Aurintricarboxylic Acid. J Biol Chem. 1998;273:28–32.CrossRefPubMed
49.
50.
Weaver AM, Silva CM. Signal transducer and activator of transcription 5b: a new target of breast tumor kinase/protein tyrosine kinase 6. Breast Cancer Res. 2007;9(6):R79.CrossRefPubMedPubMedCentral
51.
Park JH, Darvin P, Lim EJ, Joung YH, Hong DY, Park EU, et al. Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts. PLoS One. 2012;7(7), e40531.CrossRefPubMedPubMedCentral
52.
Weaver AM, Silva CM. Modulation of stat5b activity in breast cancer cells by mutation of tyrosines within the transactivation domain. Mol Endocrinol. 2006;20(10):2392–405.CrossRefPubMed
53.
Tweardy D, Chang JC. Stat5: From breast development to cancer prognosis, prediction, and progression. J Clin Oncol. 2011;29(18):2443–7.CrossRefPubMed
54.
Xiong H, Su WY, Liang QC, Zhang ZG, Chen HM, Du W, et al. Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. Lab Invest. 2009;89(6):717–25.CrossRefPubMed
55.
Bernaciak TM, Zareno J, Parsons JT, Silva CM. A novel role for signal transducer and activator of transcription 5b (STAT5b) in β1-integrin-mediated human breast cancer cell migration. Breast Cancer Res. 2009;11(4):R52.CrossRefPubMedPubMedCentral
56.
Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: Novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009;4:54–72.CrossRefPubMed
57.
Lim EJ, Joung YH, Jung SM, Park SH, Park JH, Kim SY, et al. Hemin inhibits cyclin D1 and IGF-1 expression via STAT5b under hypoxia in ERα-negative MDA-MB 231 breast cancer cells. Int J Oncol. 2010;36:1243–51.PubMed
58.
Kucab JE, Dunn SE. Role of IGF-1R in mediating breast cancer invasion and metastasis. Breast Dis. 2003;17:41–7.CrossRefPubMed
59.
Joung YH, Lee MY, Lim EJ, Kim MS, Hwang TS, Kim SY, et al. Hypoxia activates the IGF-1 expression through STAT5b in human HepG2 cells. Biochem Biophys Res Commun. 2007;358:733–8.CrossRefPubMed
60.
Berishaj M, Gao SP, Ahmed S, Leslie K, Al-Ahmadie H, Gerald WL, et al. Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res. 2007;9(3):R32.CrossRefPubMedPubMedCentral
61.
Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11(2):367–76.CrossRefPubMed
62.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21:2000–8.CrossRefPubMed
63.
Pakala SB, Rayala SK, Wang RA, Ohshiro K, Mudvari P, Reddy SD, et al. MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer. Cancer Res. 2013;73(12):3761–70.CrossRefPubMedPubMedCentral
64.
Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 2008;10:287–97.CrossRefPubMedPubMedCentral
65.
Elkin M, Orgel A, Kleinman HK. An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst. 2004;96(11):875–8.CrossRefPubMed
66.
Weigelt B, Peterse JL, van’t Veer LJ. Breast cancer metastasis: markers and models. Nature Rev Cancer. 2005;5:591–602.CrossRef
67.
Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32(50):4814–24.CrossRefPubMed
68.
Wang XF, Zhou QM, Lu YY, Zhang H, Huang S, Su SB. Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. Expert Opin Ther Targets. 2015;19(5):577–87.CrossRefPubMed
69.
Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol. 2002;3:207–14.CrossRefPubMed
70.
Scherer RL, McIntyre JO, Matrisian LM. Imaging matrix metalloproteinases in cancer. Cancer Metastasis Rev. 2008;27:679–90.CrossRefPubMed
71.
Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C. Matrixmetalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol. 2004;48:411–24.CrossRefPubMed
72.
Jones JL, Glynn P, Walker RA. Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol. 1999;189:161–8.CrossRefPubMed
73.
Kim TD, Song KS, Li G, Choi H, Park HD, Lim K, et al. Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer. BMC Cancer. 2006;6:211.CrossRefPubMedPubMedCentral
74.
Bodey B, Bodey Jr B, et al. Invasion and metastasis: the expression and significance of matrix metalloproteinases in carcinomas of the lung. In Vivo. 2001;15:175–80.PubMed
Metadata
Title
The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts
Authors
Nipin SP
Pramod Darvin
Young Beom Yoo
Youn Hee Joung
Dong Young Kang
Don Nam Kim
Tae Sook Hwang
Sang Yoon Kim
Wan Seop Kim
Hak Kyo Lee
Byung Wook Cho
Heui Soo Kim
Kyung Do Park
Jong Hwan Park
Soung Hoon Chang
Young Mok Yang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1445-0

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