Background: Leptin and leptin receptor (Ob-R) are associated with worse prognosis, distant metastasis, and poor survival of breast cancer. We investigated the cytotoxic effect of silibinin and curcumin, individually and combined, on Ob-R expression in MCF-7 cells. Methods: This study was performed from October 2017 to April 2018 at the Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. The cytotoxic effect of silibinin and curcumin, individually and combined, and their corresponding half-maximal inhibitory concentration (IC50) values were determined using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The cells were treated with different concentrations of silibinin (50-400 μM), curcumin (10-35 μM), and their combinations for 24 and 48 hours. The expression of Ob-R was measured using the Western blot analysis by treating the cells with different concentrations of curcumin (10-25 μM), silibinin (50-250 μM), and their respective combinations. The difference in mean cell viability between the groups was calculated using one-way ANOVA followed by Tukey’s post hoc test. Results: Silibinin and curcumin exerted time- and dose-dependent cytotoxic effect on MCF-7 cells. After treatment with silibinin, the IC50 values were about 250 and 50 μM at 24 and 48 hours, respectively. In terms of treatment with curcumin, the IC50 values were about 25 and 15 μM at 24 and 48 hours, respectively. Following treatment with silibinin, the Western blot analysis showed that Ob-R expression significantly decreased at 150 μM (P=0.031) and 200 μM (P=0.023) concentrations. Curcumin did not significantly decrease the Ob-R expression, however, the expression significantly decreased (P=0.004) when it was combined with silibinin. Conclusion: The combination of silibinin and curcumin significantly reduced Ob-R expression in MCF-7 cells compared with their individual effects. |
- Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66. doi: 10.3322/canjclin.57.1.43. PubMed PMID: 17237035.
- Harvie M, Hooper L, Howell AH. Central obesity and breast cancer risk: a systematic review. Obes Rev. 2003;4:157-73. doi: 10.1046/j.1467-789x.2003.00108.x. PubMed PMID: 12916817.
- Ando S, Gelsomino L, Panza S, Giordano C, Bonofiglio D, Barone I, et al. Obesity, Leptin and Breast Cancer: Epidemiological Evidence and Proposed Mechanisms. Cancers (Basel). 2019;11. doi: 10.3390/cancers11010062. PubMed PMID: 30634494; PubMed Central PMCID: PMCPMC6356310.
- Michels KB, Terry KL, Willett WC. Longitudinal study on the role of body size in premenopausal breast cancer. Arch Intern Med. 2006;166:2395-402. doi: 10.1001/archinte.166.21.2395. PubMed PMID: 17130395.
- Gu L, Wang CD, Cao C, Cai LR, Li DH, Zheng YZ. Association of serum leptin with breast cancer: A meta-analysis. Medicine (Baltimore). 2019;98:e14094. doi: 10.1097/MD.0000000000014094. PubMed PMID: 30702563; PubMed Central PMCID: PMCPMC6380739.
- Khan S, Shukla S, Sinha S, Meeran SM. Role of adipokines and cytokines in obesity-associated breast cancer: therapeutic targets. Cytokine Growth Factor Rev. 2013;24:503-13. doi: 10.1016/j.cytogfr.2013.10.001. PubMed PMID: 24210902.
- Garcia-Robles MJ, Segura-Ortega JE, Fafutis-Morris M. The biology of leptin and its implications in breast cancer: a general view. J Interferon Cytokine Res. 2013;33:717-27. doi: 10.1089/jir.2012.0168. PubMed PMID: 23869900.
- Schaffler A, Scholmerich J, Buechler C. Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab. 2007;3:345-54. doi: 10.1038/ncpendmet0456. PubMed PMID: 17377617.
- Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 2004;10:4325-31. doi: 10.1158/1078-0432.CCR-03-0749. PubMed PMID: 15240518.
- Gorska E, Popko K, Stelmaszczyk-Emmel A, Ciepiela O, Kucharska A, Wasik M. Leptin receptors. Eur J Med Res. 2010;15:50-4. doi: 10.1186/2047-783x-15-s2-50. PubMed PMID: 21147620; PubMed Central PMCID: PMCPMC4360333.
- Yom CK, Lee KM, Han W, Kim SW, Kim HS, Moon BI, et al. Leptin as a potential target for estrogen receptor-positive breast cancer. J Breast Cancer. 2013;16:138-45. doi: 10.4048/jbc.2013.16.2.138. PubMed PMID: 23843844; PubMed Central PMCID: PMCPMC3706857.
- Mohammadzadeh G, Ghaffari MA, Bafandeh A, Hosseini SM. Association of serum soluble leptin receptor and leptin levels with breast cancer. J Res Med Sci. 2014;19:433-8. PubMed PMID: 25097626; PubMed Central PMCID: PMCPMC4116575.
- Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res. 2006;12:1447-53. doi: 10.1158/1078-0432.CCR-05-1913. PubMed PMID: 16533767.
- Lee SJ, Krauthauser C, Maduskuie V, Fawcett PT, Olson JM, Rajasekaran SA. Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer. 2011;11:144. doi: 10.1186/1471-2407-11-144. PubMed PMID: 21501498; PubMed Central PMCID: PMCPMC3090367.
- Bandyopadhyay D. Farmer to pharmacist: curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer. Front Chem. 2014;2:113. doi: 10.3389/fchem.2014.00113. PubMed PMID: 25566531; PubMed Central PMCID: PMCPMC4275038.
- Falah RR, Talib WH, Shbailat SJ. Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis. Ther Adv Med Oncol. 2017;9:235-52. doi: 10.1177/1758834016687482. PubMed PMID: 28491145; PubMed Central PMCID: PMCPMC5405996.
- Patel PB, Thakkar VR, Patel JS. Cellular Effect of Curcumin and Citral Combination on Breast Cancer Cells: Induction of Apoptosis and Cell Cycle Arrest. J Breast Cancer. 2015;18:225-34. doi: 10.4048/jbc.2015.18.3.225. PubMed PMID: 26472972; PubMed Central PMCID: PMCPMC4600686.
- Nejati-Koshki K, Akbarzadeh A, Pourhassan-Moghaddam M. Curcumin inhibits leptin gene expression and secretion in breast cancer cells by estrogen receptors. Cancer Cell Int. 2014;14:66. doi: 10.1186/1475-2867-14-66. PubMed PMID: 25866478; PubMed Central PMCID: PMCPMC4392783.
- Surai PF. Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants (Basel). 2015;4:204-47. doi: 10.3390/antiox4010204. PubMed PMID: 26785346; PubMed Central PMCID: PMCPMC4665566.
- Liou W-S, Chen L-J, Niu H-S, Yang T-T, Cheng J-T, Lin K-C. Herbal product silibinin-induced programmed cell death is enhanced by metformin in cervical cancer cells at the dose without influence on nonmalignant cells. Journal of Applied Biomedicine. 2015;13:113-21. doi: org/10.1016/j.jab.2014.11.001.
- Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs. 2007;25:139-46. doi: 10.1007/s10637-006-9019-2. PubMed PMID: 17077998.
- Raina K, Agarwal R. Combinatorial strategies for cancer eradication by silibinin and cytotoxic agents: efficacy and mechanisms. Acta Pharmacol Sin. 2007;28:1466-75. doi: 10.1111/j.1745-7254.2007.00691.x. PubMed PMID: 17723180.
- Fazeli M, Zarkesh-Esfahani H, Wu Z, Maamra M, Bidlingmaier M, Pockley AG, et al. Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods. 2006;312:190-200. doi: 10.1016/j.jim.2006.03.011. PubMed PMID: 16690078.
- Revillion F, Charlier M, Lhotellier V, Hornez L, Giard S, Baranzelli MC, et al. Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers. Clin Cancer Res. 2006;12:2088-94. doi: 10.1158/1078-0432.CCR-05-1904. PubMed PMID: 16609020.
- Peters JH, Simasko SM, Ritter RC. Leptin analog antagonizes leptin effects on food intake and body weight but mimics leptin-induced vagal afferent activation. Endocrinology. 2007;148:2878-85. doi: 10.1210/en.2006-1320. PubMed PMID: 17363463; PubMed Central PMCID: PMCPMC2509585.
- Nejati-Koshki K, Zarghami N, Pourhassan-Moghaddam M, Rahmati-Yamchi M, Mollazade M, Nasiri M, et al. Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors. Cytotechnology. 2012;64:719-26. doi: 10.1007/s10616-012-9452-3. PubMed PMID: 22526491; PubMed Central PMCID: PMCPMC3488373.
- Yi KW, Shin JH, Seo HS, Lee JK, Oh MJ, Kim T, et al. Role of estrogen receptor-alpha and -beta in regulating leptin expression in 3T3-L1 adipocytes. Obesity (Silver Spring). 2008;16:2393-9. doi: 10.1038/oby.2008.389. PubMed PMID: 18719660.
- O’Neil JS, Burow ME, Green AE, McLachlan JA, Henson MC. Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta. Mol Cell Endocrinol. 2001;176:67-75. doi: 10.1016/s0303-7207(01)00473-7. PubMed PMID: 11369444.
- Wazir U, Al Sarakbi W, Jiang WG, Mokbel K. Evidence of an autocrine role for leptin and leptin receptor in human breast cancer. Cancer Genomics Proteomics. 2012;9:383-7. PubMed PMID: 23162077.
- Fusco R, Galgani M, Procaccini C, Franco R, Pirozzi G, Fucci L, et al. Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting. Endocr Relat Cancer. 2010;17:373-82. doi: 10.1677/ERC-09-0340. PubMed PMID: 20410173.
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