The Effect of Melatonin and Cisplatin Combination Using Copper-Transporting ATPase-1, P-Glycoprotein, and Gamma-Glutamylcysteinylglycine on Ovarian Cancer Biological Cell SKOV3
Keywords:Melatonin, Cisplatin, Copper-Transporting ATPase-1, p-Glycoprotein, Glutamylcysteinylglycine, SKOV3 cells
Background: Ovarian cancer is fifth most common female cancer and third most common cancer in Indonesia, but most are advanced stage patients that experiencing recurrence, which indicates resistance to treatment especially to cisplatin. Melatonin appears as an alternative that can support apoptotic effect of cisplatin as a chemotherapy regimen.
Aim: To determine effect of combination melatonin and cisplatin compared with cisplatin only chemotherapy on chemotherapy resistance with Copper Transporting ATPase-1 (CTR-1), P-glycoprotein (P-Gp), and Gamma-Glutamylcysteinylglycine (GSH) biomarkers in ovarian cancer biological cells SKOV3
Methods: This research design was experimental laboratory, post-test only control group design, using SKOV3 cell culture. This study was performed in the SCTE IMERI FKUI laboratory and Integrated Laboratory FKUI. MTS assay was used to calculate IC50 of each materials. The materials used were melatonin (concentration was 25,50,100,200,300 nM), cisplatin (concentration was 0.1, 0.5, 1, 2, 5 mM), and doxorubicin (concentration 10,20,40,50,80,100,200 µM). IC50 melatonin was 1,841 mM, IC50 cisplatin was 117,5 µM, and IC50 doxorubicin was 14,72 µM. Samples were control negative group, IC50 doxorubicin as a control positive, IC50 cisplatin, IC50 melatonin, combination group of melatonin and cisplatin were 1xIC50, ¾xIC50, ½xIC50, and ¼xIC50. ANOVA and Bonferroni test were used for statistical test.
Results: Based on data processing, IC50 of melatonin was 1,841 mM, IC50 of doxorubicin was 14,72 mM, while IC50 of cisplatin was 117.5 μM. The mean expression of CTR-1 in IC50 melatonin group was 15.77 ± 0.21 and in IC50 cisplatin group was 10.87 ± 0.91, mean expression in IC50 doxorubicin group was 30,33 ± 0,4. Meanwhile, mean expression of CTR-1 in IC50 cisplatin was 7,37±0,7, and in combination 1 group (1xIC50 melatonin and 1xIC50 cisplatin) was 19,73±1.0,49. For P glycoprotein, mean expression in IC50 cisplatin was 16±1,59, in IC50 melatonin group was 7,37±0,21, in IC50 doxorubicin was 0, and in combination 1 group (1xIC50 melatonin and 1xIC50 cisplatin) was 6,7±0,17. Last, in GSH, mean expression in IC50 cisplatin group was 33,2±0,87, in IC50 melatonin group was 12,57±0,12, in IC50 doxorubicin group was 1,33±0,66, and in combination 1 group (1xIC50 melatonin and 1xIC50 cisplatin) was 11,73±0,67. There was significant difference of CTR-1 expression in combination 1 group which was higher (19.73%), p-glycoprotein expression in combination 1 group which was lower (6,7%), and also GSH expression in combination 1 group was lower (11,73%) compared to other groups.
Conclusion: The group 1 combination of 1xIC50 melatonin and 1x IC50 cislatin with 1.841 mM and cisplatin 117.5 uM were able to reduce cisplatin chemotherapy resistance by increasing drug influx activity by increasing CTR-1 expression, decreasing drug efflux through decreasing p-glycoprotein expression, and decreased DNA repair activity through decreased GSH expression.
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre AL, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worlwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. https://doi.org/10.3322/caac.21492 PMid:30207593 DOI: https://doi.org/10.3322/caac.21492
Indonesia Society of Gynecologic Oncology. National Data, 2000-2016. Available from: http://inasgo.org [Last accessed on 2021 Aug 20].
Tapia G, Padilla I. Molecular mechanism of platinum resistance in ovarian cancer. In: Ovarian Cancer: A Clinical and Translational Update. Ch. 10. London: InTech DTP Team; 2013. p. 205-9. https://doi.org/10.5772/55562 DOI: https://doi.org/10.5772/55562
Damia G, Broggini M. Platinum resistance in ovarian cancer: Role of DNA repair. Cancers. 2019;11(1):119. https://doi.org/10.3390/cancers11010119 PMid:30669514 DOI: https://doi.org/10.3390/cancers11010119
Sousa GF, Wlodarczyk S, Monteiro G. Carboplatin: molecular mechanisms of action associated with chemoresistance. Braz J Pharm Sci. 2014;50:694-7. https://doi.org/10.1590/s1984-82502014000400004 DOI: https://doi.org/10.1590/S1984-82502014000400004
Chen HW, Kuo MT. Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy. Metal Based Drugs 2010;2010:430939. https://doi.org/10.1155/2010/430939 PMid:20885916 DOI: https://doi.org/10.1155/2010/430939
Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre M, Qin L. Melatonin as an antioxidant: Under promises but over delivers. J Pineal Res. 2016;61(3):253-78. https://doi.org/10.1111/jpi.12360 PMid:27500468 DOI: https://doi.org/10.1111/jpi.12360
Favero G, Moretti E, Bonomini F, Reiter RJ, Rodella RF, Rezzani R. Promising antineoplastic actions of melatonin. Front Pharmacol. 2018:9:1086. https://doi.org/10.3389/fphar.2018.01086 PMid:30386235 DOI: https://doi.org/10.3389/fphar.2018.01086
Chuffa L, Reiter R, Lupi L. Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. Carcinogenesis. 2017;38(10):945-52. https://doi.org/10.1093/carcin/bgx054 PMid:28575150 DOI: https://doi.org/10.1093/carcin/bgx054
Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24):39896-921. https://doi.org/10.18632/oncotarget.16379 PMid:28415828 DOI: https://doi.org/10.18632/oncotarget.16379
Yang T, Chen M, Chen T, Thakur A. Expression of the copper transporters hCTR-1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer. Oncol Lett. 2015;10(4):2584-90. https://doi.org/10.3892/ol.2015.3531 PMid:26622894 DOI: https://doi.org/10.3892/ol.2015.3531
Zhang X, Hou G, Liu A, Xu H, Guan Y, Wu Y, et al. Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways. Cell Death Dis. 2019;10(10):770. https://doi.org/10.1038/s41419-019-2013-3 PMid:31601793 DOI: https://doi.org/10.1038/s41419-019-2013-3
He C, Sun Z, Hoffman R, Yang Z, Jiang Y, Wang L. P-glycoprotein overexpression is associated with cisplatin resistance in human osteosarcoma. Anti Cancer Res. 2019;39(4):1711-8. https://doi.org/10.21873/anticanres.13277 PMid:30952710 DOI: https://doi.org/10.21873/anticanres.13277
Kilari D, Guancial E, Kim ES. Role of copper transporters in platinum resistance. World J Clin Oncol. 2016;7(1):106-13. https://doi.org/10.5306/wjco.v7.i1.106 DOI: https://doi.org/10.5306/wjco.v7.i1.106
Silva MM, Rocha CR, Kinker GS, Pelegrini AL, Menck CF. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci Rep. 2019;9:17639. https://doi.org/10.1038/s41598-019-54065-6 DOI: https://doi.org/10.1038/s41598-019-54065-6
Kalayda GV, Wagner CH, Jaehde U. Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells. J Inorg Biochem. 2012;116:1-10. https://doi.org/10.1016/j.jinorgbio.2012.07.010 PMid:23010323 DOI: https://doi.org/10.1016/j.jinorgbio.2012.07.010
Liu K, Song J, Yan T, Zou K, Che Y, Wang B, et al. Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin by inhibiting P-glycoprotein expression via the NF-κB pathway. Transl Oncol. 2021;14(1):100876. https://doi.org/10.1016/j.tranon.2020.100876 PMid:33007707 DOI: https://doi.org/10.1016/j.tranon.2020.100876
Yang X, Ding Y, Xiao M, Liu X, Ruan J, Xue P. Anti-tumor compound RY10-4 suppresses multidrug resistance in MCF-7/ADR cells by inhibiting PI3K/Akt/NF-κB signaling. Chem Biol Interact. 2017;278:22-31. https://doi.org/10.1016/j.cbi.2017.10.008 PMid:28987325 DOI: https://doi.org/10.1016/j.cbi.2017.10.008
Kim JH, Kim SW, Hong JY, Ryu KJ, Kim SJ, Park C. Epstein-Barr virus EBNA2 directs doxorubicin resistance of B cell lymphoma through CCL3 and CCL4-mediated activation of NF-κB and Btk, Oncotarget. 2017;8(3):5361-70. https://doi.org/10.18632/oncotarget.14243 PMid:28036258 DOI: https://doi.org/10.18632/oncotarget.14243
Jamali B, Nakhjavani M, Hosseinzadeh L, Amidi S, Nikounezhad N, Shirazi FH. Intracellular GSH alterations and its relationship to level of resistance following exposure to cisplatin in cancer cells. Iran J Pharm Res. 2015;14(2):513-9. PMid:25901159
Medina-Leendertz S, Mora M, Vielma JR, Bravo Y, Atencio-Bracho L, Leal-Yépez A, et al. Melatonin decreases oxidative stress in Drosophila melanogaster exposed to manganese. Investig Cl.n. 2018;59(3):230-41. https://doi.org/10.22506/ti/2017/v24/i1/149037 DOI: https://doi.org/10.22506/ti/2017/v24/i1/149037
Fernandez-Gil BI, Guerra-Librero A, Shen YQ, Florido J, Martinez-Ruiz L, García-López S, et al. Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. Oxid Med Cell Longev. 2019;2019:7187128. https://doi.org/10.1155/2019/7187128 DOI: https://doi.org/10.1155/2019/7187128
Harderland R. Melatonin and the electron transport chain. Cell Mol Life Sci. 2019;74(21):3883-96. https://doi.org/10.1007/s00018-017-2615-9 DOI: https://doi.org/10.1007/s00018-017-2615-9
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