Abstract
Arbutin is one of the active ingredients employed in cosmetics as a skin whitening agent. In the present study, the possible effects of arbutin on breast cancer were determined with human breast adenocarcinoma (MCF-7) cells. α and β-arbutin cytotoxicity levels in MCF-7 cells were determined with the MTT method. At low (1–10 mM) doses, α-arbutin appears to be more toxic than β-arbutin. At higher (5–200 mM) and LD50 doses beta arbutin toxicity appears to be higher than alpha arbutin. Thus, the study was continued with β -arbutin. The effects of low and high doses of β-arbutin was determined on oxidative stress, genotoxicity, inflammation, apoptosis, proliferation, endoplasmic reticulum stress and estrogen receptor-α in MCF-7 cells. The results demonstrated that the β-arbutin doses administered to MCF-7 cells did not affect oxidative and endoplasmic reticulum stress in the experimental groups. However, it was found that administration of LD50 dose β-arbutin induced inflammation in these cells via proinflammatory cytokine levels (TNF-α, IFN-γ and IL-1β). It was observed that LD10 and LD50 doses of β-arbutin increased genotoxicity in MCF-7 cells. The gene expression analysis conducted with RT-PCR device and immunocytochemical analysis revealed that β-arbutin at LD50 dose induced apoptosis in MCF-7 cells via p53 and Caspase 3. Furthermore, it was determined that all β-arbutin doses inhibited estrogen receptor-α in MCF-7 cells. Considering that arbutin increased the activation of apoptotic Caspase 3 through p53, which was stimulated by genotoxic and inflammatory effects at LD50 dose in MCF-7 cells. Determination of this mechanism behind these effects of β-arbutin may contribute to the development of a new perspective in treatment.
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References
Couteau C, Coiffard L (2016) Overview of skin whitening agents: drugs and cosmetic products. Cosmetics 3(3):27. https://doi.org/10.3390/cosmetics3030027
Cheng SL, Liu RH, Sheu JN, Chen ST, Sinchaikul S, Tsay GJ (2007) Toxicogenomics of A375 human malignant melanoma cells treated with arbutin. J Biomed Sci 14(1):87–105. https://doi.org/10.1007/s11373-006-9130-6
Nordlund JJ, Grimes PE, Ortonne JP (2006) The safety of hydroquinone. J Eur Acad Dermatol Venereol 20(7):781–787. https://doi.org/10.1111/j.1468-3083.2006.01670.x
Westerhof W, Kooyers TJ (2005) Hydroquinone and its analogues in dermatology-a potential health risk. J Cosmet Dermatol 4(2):55–59. https://doi.org/10.1111/j.1473-2165.2005.40202.x
Horita M, Wang DH, Tsutsui K, Sano K, Masuoka N, Kiraet S (2005) Involvement of oxidative stress in hydroquinone-induced cytotoxicity in catalase-deficient Escherichia coli mutants. Free Radic Res 39:1035–1041. https://doi.org/10.1080/1071576050023200
Jurica K, Karačonji IB, Benković V, Kopjar N (2017) In vitro assessment of the cytotoxic, DNA damaging, and cytogenetic effects of hydroquinone in human peripheral blood lymphocytes. Asian Pac J Cancer Prev 68(4):322–335. https://doi.org/10.1515/aiht-2017-68-3060
Levitt J (2007) The safety of hydroquinone: a dermatologist’s response to the 2006 Fedral Register. J Am Acad Dermatol 57(5):854–872. https://doi.org/10.1016/j.jaad.2007.02.020
Boissy RE, Visscher M, DeLong MA (2005) DeoxyArbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Exp Dermatol. https://doi.org/10.1111/j.0906-6705.2005.00337.x
Hu ZM, Zhou Q, Lei TC, Ding SF, Xu SZ (2009) Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: biosafety as skin whitening agents. J Dermatol Sci 55:179–184. https://doi.org/10.1016/j.jdermsci.2009.06.003
Miao F, Shi Y, Fan ZF, Jiang S, Xu SZ, Lei TC (2016) Deoxyarbutin possesses a potent skin-lightening capacity with no discernible cytotoxicity against melanosomes. PLoS ONE 11(10):e0165338. https://doi.org/10.1371/günlük.pone.0165338
Zhu X, Tian Y, Zhang W, Zhang T, Guang C, Mu W (2018) Recent progress on biological production of α-arbutin. Appl Microbiol Biotechnol 102(19):8145–8152. https://doi.org/10.1007/s00253-018-9241-9
Ulasli SS, Celik S, Gunay E, Ozdemir M, Hazman O, Ozyurek A, Koyuncu T, Unlu M (2013) Anticancer effects of thymoquinone, caffeic acid phenethyl ester and resveratrol on A549 non-small cell lung cancer cells exposed to benzo(a)pyrene. Asian Pac J Cancer Prev 14(10):6159–6164. https://doi.org/10.7314/apjcp.2013.14.10.6159
Ersin G, Çelik S, Ulasli SS, Özyürek A, Hazman Ö, Günay S, Özdemir M, Ünlü M (2016) Comparison of the anti-inflammatory effects of proanthocyanidin, quercetin, and damnacanthal on benzo(a)pyrene exposed A549 alveolar cell line. Inflammation 39(2):744–751. https://doi.org/10.1007/s10753-015-0301-3
Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191. https://doi.org/10.1016/0014-4827(88)90265-0
Fenech M (2000) The in vitro micronucleus technique. Mutat Res 455:81–95. https://doi.org/10.1016/S0027-5107(00)00065-8
Hazman Ö, Aksoy L, Büyükben A (2016) Effects of crocin on experimental obesity and type-2 diabetes. Turk J Med Sci 46(5):1593–1602. https://doi.org/10.3906/sarkma-1506-108
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45. https://doi.org/10.1093/nar/29.9.e45
Berdowska I, Zieliński B, Fecka I, Kulbacka J, Saczko J, Gamian A (2013) Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chem 141(2):1313–1321. https://doi.org/10.1016/j.foodchem.2013.03.090
Garcia-Jimenez A, Teruel-Puche JA, Berna J, Rodriguez-Lopez JN, Tudela J, Garcia-Canovas F (2017) Action of tyrosinase on alpha and beta-arbutin. PLoS ONE 12(5):e0177330. https://doi.org/10.1371/journal.pone.0177330
Sugimoto K, Nishimura T, Nomura K, Sugimoto K, Kuriki T (2003) Syntheses of arbutin-alpha-glycosides and a comparison of their inhibitory effects with those of alpha-arbutin and arbutin on human tyrosinase. Chem Pharm Bull 51(7):798–801. https://doi.org/10.1248/cpb.51.798
Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B, Lei Y, Du S, Vuppalapati A, Luu HH, Haydon RC, He TC, Ren G (2018) Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis 5(2):77–106. https://doi.org/10.1016/j.gendis.2018.05.001
Carroll JS (2016) Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer. Eur J Endocrinol 175(1):41–49. https://doi.org/10.1530/EJE-16-0124
Bean LA, Ianov L, Foster TC (2014) Estrogen receptors, the hippocampus, and memory. Neuroscientist 20(5):534–545. https://doi.org/10.1177/1073858413519865
Gompel A, Somaï S, Chaouat M, Kazem A, Kloosterboer HJ, Beusman I, Forgez P, Mimoun M, Rostène W (2000) Hormonal regulation of apoptosis in breast cells and tissues. Steroids 65(10–11):593–598. https://doi.org/10.1016/S0039-128X(00)00172-0
Zeng M, Zhang L, Li M, Zhang B, Zhou Ke Y, Feng W, Zheng X (2018) Estrogenic effects of the extracts from the Chinese Yam (Dioscorea opposite Thunb.) and ıts effective compounds in vitro and in vivo. Molecules 23(2):11. https://doi.org/10.3390/molecules23020011
Sheikholeslami A, Nabiuni M, Arefian E (2017) Suppressing the molecular signaling pathways involved in inflammation and cancer in breast cancer cell lines MDA-MB-231 and MCF-7 by miR-590. Tumour Biol. https://doi.org/10.1177/1010428317697570
Li W, Song K, Wang S, Zhang C, Zhuang M, Wang Y, Li T (2019) Anti-tumor potential of astragalus polysaccharides on breast cancer cell line mediated by macrophage activation. Mater Sci Eng C Mater Biol Appl 98:685–695. https://doi.org/10.1016/j.msec.2019.01.025
Motaghed M, Al-Hassan FM, Hamid SS (2014) Thymoquinone regulates gene expression levels in the estrogen metabolic and interferon pathways in MCF7 breast cancer cells. Int J Mol Med 33(1):8–16. https://doi.org/10.3892/ijmm.2013.1563
Wahyu W, Harry M, Diana KJ, Sutiman B, Sumitro M, Aris W, Nurul F, Maesaroh M, Indra B (2016) Selective cytotoxic potential of IFN-γ and TNF-α on breast cancer cell lines (T47D and MCF7). Asian J Cell Biol 11(1):1–12. https://doi.org/10.3923/ajcb.2016.1.12
Lv L, Zhang J, Tian F, Li X, Li D, Yu X (2019) Arbutin protects HK-2 cells against high glucose-induced apoptosis and autophagy by up-regulating microRNA-27a. Artif Cells Nanomed Biotechnol 47(1):2940–2947. https://doi.org/10.1080/21691401.2019.1640231
Zhao W, Wang S, Qin T, Wang W (2019) Arbutin attenuates hydrogen peroxide-induced oxidative injury through regulation of microRNA-29a in retinal ganglion cells. Biomed Pharmacother 112:108729. https://doi.org/10.1016/j.biopha.2019.108729
Schröder L, Marahrens P, Koch JG, Heidegger H, Vilsmeier T, Phan-Brehm T, Hofmann S, Mahner S, Jeschke U, Richter DU (2019) Effects of green tea, matcha tea and their components epigallocatechin gallate and quercetin on MCF–7 and MDA-MB-231 breast carcinoma cells. Oncol Rep 41(1):387–396. https://doi.org/10.3892/or.2018.6789
Khorsandi L, Orazizadeh M, Niazvand F, Abbaspour MR, Mansouri E, Khodadadi A (2017) Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells. Bratisl Lek Listy 118(2):123–128. https://doi.org/10.4149/BLL_2017_025
Calaf GM, Ponce-Cusi R, Carrión F (2018) Curcumin and paclitaxel induce cell death in breast cancer cell lines. Oncol Rep 40(4):2381–2388. https://doi.org/10.3892/or.2018.6603
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This work was supported by Scientific Research Projects Committee (Project Number: 16.FEN.BIL.15) by the Rectorate of Afyon Kocatepe University, Afyonkarahisar, Turkey.
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Hazman, Ö., Sarıova, A., Bozkurt, M.F. et al. The anticarcinogen activity of β-arbutin on MCF-7 cells: Stimulation of apoptosis through estrogen receptor-α signal pathway, inflammation and genotoxicity. Mol Cell Biochem 476, 349–360 (2021). https://doi.org/10.1007/s11010-020-03911-7
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DOI: https://doi.org/10.1007/s11010-020-03911-7