Piperine Acts as an Anticancer Agent by Reducing Cyclooxygenase-2 Activity and Inducing Apoptosis by Activating p53 in HeLa Cells
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Abstract
Cervical cancer is a malignant disease with the highest incidence in women worldwide. Human papillomavirus (HPV) infection causes cancer through degradation and decreased activity of the p53 gene, which is a significant contributor to the apoptosis pathway and a major factor in cancer
incidence. In addition to p53, the cyclooxygenase-2 (COX-2) enzyme is essential for tumor formation via inflammatory pathways, particularly in cervical cancer caused by persistent HPV infection. This study aims to investigate how piperine treatment affects the HeLa cervical cancer cell line p53 expression, COX-2 levels, and cell proliferation. HeLa cells were divided into treated
groups (65 and 130 µg/mL) and an untreated group as a control group. Its activity on COX-2 levels was further analyzed using the ELISA method and gene expression using the Livak qPCR method. Cell proliferation can be inhibited by piperine, with an IC50 value of 66.68 µg/ml. Piperine can also increase p53 gene expression and suppress COX-2 levels in HeLa cells. Piperine has cell
growth inhibitory activity, suppresses the inflammatory process by reducing COX-2 enzyme levels, and induces apoptosis through upregulation of the p53 gene.
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Vu M, Yu J, Awolude OA, Chuang L. Cervical cancer worldwide. Curr Probl Cancer. 2018;42(5):457-465. doi:10.1016/j.currproblcancer.2018.06.003
Manzo-Merino J, Contreras-Paredes A, Vázquez-Ulloa E, Rocha-Zavaleta L, Fuentes-Gonzalez AM, Lizano M. The Role of Signaling Pathways in Cervical Cancer and Molecular Therapeutic Targets. Arch Med Res. 2014;45(7):525-539. doi:10.1016/j.arcmed.2014.10.008
Bruni L, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. Human Papillomavirus and Related Diseases Report. ICO/IARC Inf Cent HPVand Cancer (HPV Inf Centre). 2019;307. https://hpvcentre.net/statistics/reports/XWX.pdf
Prati B, Marangoni B, Boccardo E. Human papillomavirus and genome instability: From productive infection to cancer. Clinics. 2018;73(6):1-9. doi:10.6061/clinics/2018/e539s
Garima, Pandey S, Pandey LK, Saxena AK, Patel N. The Role of p53 Gene in Cervical Carcinogenesis. J Obstet Gynecol India. 2016;66(1):383-388. doi:10.1007/s13224-015-0754-1
Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta - Mol Cell Res. 2016;1863(12):2977-2992. doi:10.1016/j.bbamcr.2016.09.012
Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - The p53 network. J Cell Sci. 2003;116(20):4077-4085. doi:10.1242/jcs.00739
O’Connor L, Harris AW, Strasser A. CD95 (Fas/APO-1) and p53 signal apoptosis independently in diverse cell types. Cancer Res. 2000;60(5):1217-1220.
Han YH, Wang Y, Lee SJ, Jin MH, Sun HN, Kwon T. Regulation of anoikis by extrinsic death receptor pathways. Cell Commun Signal. 2023;21(1):1-14. doi:10.1186/s12964-023-01247-5
Lalaoui N, Vaux DL. Recent advances in understanding inhibitor of apoptosis proteins. F1000Research. 2018;7(0):1-15. doi:10.12688/f1000research.16439.1
Bourdon JC, Renzing J, Robertson PL, Fernandes KN, Lane DP. Scotin, a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J Cell Biol. 2002;158(2):235-246. doi:10.1083/jcb.200203006
Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25(1):104-113. doi:10.1038/cdd.2017.169
Hidalgo-Estévez AM, Stamatakis K, Jiménez-Martínez M, López-Pérez R, Fresno M. Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer. Front Pharmacol. 2020;11:1-13. doi:10.3389/fphar.2020.00533
Rehmat J, Chaudhry G e S. Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics. Adv Pharm Bull. 2019;9(2):205-218. doi:10.15171/jcvtr.2015.24
Engel N, Oppermann C, Falodun A, Kragl U. Proliferative effects of five traditional Nigerian medicinal plant extracts on human breast and bone cancer cell lines. J Ethnopharmacol. 2011;137(2):1003-1010. doi:10.1016/j.jep.2011.07.023
Engel N, Falodun A, Kühn J, Kragl U, Langer P, Nebe B. Pro-apoptotic and anti-adhesive effects of four African plant extracts on the breast cancer cell line MCF-7. BMC Complement Altern Med. 2014;14(1):1-13. doi:10.1186/1472-6882-14-334
Gewin L, Myers H, Kiyono T, Galloway DA. Identification of a novel telomerase E6/E6-AP complexIdentification of a novel telomerase E6/E6-AP complex. 2004;3:1-14. doi:10.1101/gad.1214704.cells
Chopra B, Dhingra AK, Kapoor RP, Prasad DN. Piperine and Its Various Physicochemical and Biological Aspects: A Review. Open Chem J. 2017;3(1):75-96. doi:10.2174/1874842201603010075
Han S zhai, Liu H xia, Yang L qing, Cui L de, Xu Y. Piperine(PP) enhanced mitomycin-C (MMC) therapy of human cervical cancer through suppressing Bcl-2 signaling pathway via inactivating STAT3/NF-κB. Biomed Pharmacother. 2017;96:1403-1410. doi:10.1016/j.biopha.2017.11.022
Landskron G, De La Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014. doi:10.1155/2014/149185
Lin M, Ye M, Zhou J, Wang ZP, Zhu X. Recent Advances on the Molecular Mechanism of Cervical Carcinogenesis Based on Systems Biology Technologies. Comput Struct Biotechnol J. 2019;17(109):241-250. doi:10.1016/j.csbj.2019.02.001
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101-1108. doi:10.1038/nprot.2008.73
Kamiloglu S, Sari G, Ozdal T, Capanoglu E. Guidelines for cell viability assays. Food Front. 2020;1(3):332-349. doi:10.1002/fft2.44
Van Tonder A, Joubert AM, Cromarty AD. Limitations of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2Htetrazolium bromide (MTT) assay when compared to three commonly used cell enumeration assays. BMC Res Notes. 2015;8(1):1-10. doi:10.1186/s13104-015-1000-8
Ghasemi M, Turnbull T, Sebastian S, Kempson I. The mtt assay: Utility, limitations, pitfalls, and interpretation in bulk and single-cell analysis. Int J Mol Sci. 2021;22(23). doi:10.3390/ijms222312827
He Y, Zhu Q, Chen M, Huang Q, Wang W, Li Q, Huang Y, Di W. The changing 50% inhibitory concentration (IC50) of cisplatin: A pilot study on the artifacts of the MTT assay and the precise measurement of density-dependent chemoresistance in ovarian cancer. Oncotarget. 2016;7(43):70803-70821. doi:10.18632/oncotarget.12223
Wang Q, Morris RJ, Bode AM, Zhang T. Prostaglandin Pathways: Opportunities for Cancer Prevention and Therapy. Cancer Res. 2022;82(6):949-965. doi:10.1158/0008-5472.CAN-21-2297
Tai HH, Ensor CM, Tong M, Zhou H, Yan F. Prostaglandin catabolizing enzymes. Prostaglandins Other Lipid Mediat. 2002;68-69:483-493. doi:10.1016/S0090-6980(02)00050-3
Ghosh N, Chaki R, Mandal V, Mandal SC. Cox-2 as a target for cancer chemotherapy. Pharmacol Reports. 2010;62(2):233-244. doi:10.1016/S1734-1140(10)70262-0
Khan Z, Khan N, P. Tiwari R, K. Sah N, Prasad G, S. Bisen P. Biology of Cox-2: An Application in Cancer Therapeutics. Curr Drug Targets. 2011;12(7):1082-1093. doi:10.2174/138945011795677764
Lanas A, Wu P, Medin J, Mills EJ. Low Doses of Acetylsalicylic Acid Increase Risk of Gastrointestinal Bleeding in a Meta-Analysis. Clin Gastroenterol Hepatol. 2011;9(9):762-768. doi:10.1016/j.cgh.2011.05.020
Pan J,Yang Q, Shao J, Zhang L, Ma J, Wang Y, Jiang BH, Leng J, Bai X. Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway. Sci Rep. 2016;6:1-12. doi:10.1038/srep33823
Cardoso LP, de Sousa SO, Gusson-Zanetoni JP, de Melo Moreira Silva LL, Frigieri BM, Henrique T, Tajara EH, Oliani SM, Rodrigues-Lisoni FC. Piperine Reduces Neoplastic Progression in Cervical Cancer Cells by Downregulating the Cyclooxygenase 2 Pathway. Pharmaceuticals. 2023;16(1). doi:10.3390/ph16010103
Kim HG, Han EH, Jang WS, Choi JH, Khanal T, Park BH, Tran TP, Chung YC, Jeong HG. Piperine inhibits PMAinduced cyclooxygenase-2 expression through downregulating NF-κB, C/EBP and AP-1 signaling pathways in murine macrophages. Food Chem Toxicol. 2012;50(7):2342-2348. doi:10.1016/j.fct.2012.04.024
Olusola P, Banerjee HN, Philley J V, Dasgupta S. Human Papilloma Virus-Associated Cervical Cancer and Health Disparities. Cells. 2019;8(6):622. doi:10.3390/cells8060622
Medda A, Duca D, Chiocca S. Human papillomavirus and cellular pathways: Hits and targets. Pathogens. 2021;10(3):1-23. doi:10.3390/pathogens10030262
Balasubramaniam SD, Balakrishnan V, Oon CE, Kaur G. Key Molecular Events in Cervical Cancer Development. Medicina (B Aires). 2019;55(7):384. doi:10.3390/medicina55070384
Tomaić V. Functional roles of E6 and E7 oncoproteins in HPV-induced malignancies at diverse anatomical sites. Cancers (Basel). 2016;8(10). doi:10.3390/cancers8100095
Martinez-Zapien D, Ruiz FX, Poirson J, Mitschler A, Ramirez J, Forster A, Cousido-Siah Alexandra, Masson M, Pol SV, Podjarny A, Trave G, Zanier K. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature. 2016;529(7587):541-545. doi:10.1038/nature16481
Qin JJ, Li X, Hunt C, Wang W, Wang H, Zhang R. Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine. Genes Dis. 2018;5(3):204-219. doi:10.1016/j.gendis.2018.07.002
Drayman N, Ben-nun-Shaul O, Butin-Israeli V, Srivastava R, Rubinstein AM, Mock CS, Elyada E, Ben-Neriah Y, Lahav G, Oppenheim. P53 elevation in human cells halt SV40 infection by inhibiting T-ag expression. Oncotarget. 2016;7(33):52643-52660. doi:10.18632/oncotarget.10769
Williams AB, Schumacher B. p53 in the DNA-damagerepair process. Cold Spring Harb Perspect Med. 2016;6(5):1-15. doi:10.1101/cshperspect.a026070
Agu KC, Okolie NP, Falodun A, Engel-Lutz N. In vitro anticancer assessments of Annona muricata fractions and in vitro antioxidant profile of fractions and isolated acetogenin (15-acetyl guanacone). J Cancer Res Pract. 2018;5(2):53-66. doi:10.1016/j.jcrpr.2017.12.001
Lacroix M, Riscal R, Arena G, Linares LK, Le Cam L. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. Mol Metab. 2020;33:2-22. doi:10.1016/j.molmet.2019.10.002
Yue X, Zhao Y, Xu Y, Zheng M, Feng Z, Hu W. Mutant p53 in cancer: accumulation, gain-of-function and therapy. J Mol Biol. 2017;429(11):1595-1606. doi:10.1016/j.jmb.2017.03.030
Mahmood MA, Abd AH, Kadhim EJ. Investigating the Impact of Phenolic and Terpene Fractions extracted from Prunus arabica on p53 Protein Expression in AMJ13 and SKGT-4 Human Cancer Cell Lines. Trop J Nat Prod Res. 2023;7(11):5266-5269. doi:10.12688/f1000research.131336.2
Lin Y, Xu J, Liao H, Li L, Pan L. Piperine induces apoptosis of lung cancer A549 cells via p53-dependent mitochondrial signaling pathway. Tumor Biol. 2014;35(4):3305-3310. doi:10.1007/s13277-013-1433-4