Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

General Research Article

Maslinic Acid Inhibits Cervical Intraepithelial Neoplasia by Suppressing Interleukin- 6 and Enhancing Apoptosis in a Mouse Model

Author(s): Jiuwei Chen and Lin Wang*

Volume 22, Issue 3, 2022

Published on: 03 September, 2021

Page: [579 - 585] Pages: 7

DOI: 10.2174/1871520621666210903143922

Price: $65

conference banner
Abstract

Background: Cervical Intraepithelial Neoplasia (CIN) directly precedes cervical cancer, and elevated proinflammatory cytokine Interleukins (IL)-6 is implicated in CIN.

Objective: As maslinic acid exhibits anti-IL-6 property, the present study sought to determine the effect of maslinic acid on CIN in vitro and in vivo using cell cultures and mouse CIN models, respectively.

Methods: The dose-effect of maslinic acid on HeLa cells, a human cervical cancer cell line, was first evaluated, including cytotoxicity, IL-6 secretion, IL-6 receptor (IL-6R) expression, proliferation potential and apoptosis status. A mouse model of CIN was also established, which was then subjected to increasing doses of maslinic acid treatment, followed by assessment of serum IL-6 level, cervical expression of IL-6R, and the proliferation potential and apoptosis of cervical tissues.

Results: Maslinic acid dose-dependently inhibited cell growth and proliferation potential, reduced IL-6 secretion, cervical expression of IL-6R and induced apoptosis of HeLa cells in vitro. In the CIN mouse model, serum IL-6 level and cervical expression of IL-6R were elevated, which could be repressed by maslinic acid administration dosedependently. Additionally, maslinic acid treatment in the CIN mice could also restore the otherwise increased proliferation potential and reduced apoptosis in the cervical tissues.

Conclusion: Maslinic acid exhibits potent anti-IL-6 property in the CIN mouse model, and alleviates the diseaserelated abnormality in proliferation potential and apoptosis state of the cervical tissue cells, demonstrating its usefulness as a promising agent in treating CIN.

Keywords: Cervical intraepithelial neoplasia, maslinic acid, interleukin-6, apoptosis, proliferating cellular nuclear antigen, cervical tissue cells.

Graphical Abstract
[1]
Haas, J.F. Pregnancy in association with a newly diagnosed cancer: a population-based epidemiologic assessment. Int. J. Cancer, 1984, 34(2), 229-235.
[http://dx.doi.org/10.1002/ijc.2910340214] [PMID: 6469398]
[2]
Smith, L.H.; Danielsen, B.; Allen, M.E.; Cress, R. Cancer associated with obstetric delivery: results of linkage with the California cancer registry. Am. J. Obstet. Gynecol., 2003, 189(4), 1128-1135.
[http://dx.doi.org/10.1067/S0002-9378(03)00537-4] [PMID: 14586366]
[3]
Morimura, Y.; Fujimori, K.; Soeda, S.; Hashimoto, T.; Takano, Y.; Yamada, H.; Yanagida, K.; Sato, A. Cervical cytology during pregnancy-comparison with non-pregnant women and management of pregnant women with abnormal cytology. Fukushima J. Med. Sci., 2002, 48(1), 27-37.
[http://dx.doi.org/10.5387/fms.48.27] [PMID: 12365596]
[4]
McIntyre-Seltman, K.; Lesnock, J.L. Cervical cancer screening in pregnancy. Obstet. Gynecol. Clin. North Am., 2008, 35(4), 645-658.
[http://dx.doi.org/10.1016/j.ogc.2008.10.003] [PMID: 19061823]
[5]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[6]
Mitra, A.; Tzafetas, M.; Lyons, D.; Fotopoulou, C.; Paraskevaidis, E.; Kyrgiou, M. Cervical intraepithelial neoplasia: screening and management. Br. J. Hosp. Med. (Lond.), 2016, 77(8), C118-C123.
[http://dx.doi.org/10.12968/hmed.2016.77.8.C118] [PMID: 27487071]
[7]
Dunne, E.F.; Unger, E.R.; Sternberg, M.; McQuillan, G.; Swan, D.C.; Patel, S.S.; Markowitz, L.E. Prevalence of HPV infection among females in the United States. JAMA, 2007, 297(8), 813-819.
[http://dx.doi.org/10.1001/jama.297.8.813] [PMID: 17327523]
[8]
Castle, P.E.; Solomon, D.; Schiffman, M.; Wheeler, C.M. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J. Natl. Cancer Inst., 2005, 97(14), 1066-1071.
[http://dx.doi.org/10.1093/jnci/dji186] [PMID: 16030304]
[9]
Diehl, S.; Rincón, M. The two faces of IL-6 on Th1/Th2 differentiation. Mol. Immunol., 2002, 39(9), 531-536.
[http://dx.doi.org/10.1016/S0161-5890(02)00210-9] [PMID: 12431386]
[10]
Asschert, J.G.; Vellenga, E.; Ruiters, M.H.; de Vries, E.G. Regulation of spontaneous and TNF/IFN-induced IL-6 expression in two human ovarian-carcinoma cell lines. Int. J. Cancer, 1999, 82(2), 244-249.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19990719)82:2<244:AID-IJC15>3.0.CO;2-N] [PMID: 10389759]
[11]
Smola-Hess, S.; Sandaradura de Silva, U.; Hadaschik, D.; Pfister, H.J. Soluble Interleukin- 6 receptor activates the human papillomavirus type 18 long control region in SW756 cervical carcinoma cells in a STAT3-dependent manner. J. Gen. Virol., 2001, 82(Pt 10), 2335-2339.
[http://dx.doi.org/10.1099/0022-1317-82-10-2335] [PMID: 11562527]
[12]
Hess, S.; Smola, H.; Sandaradura De Silva, U.; Hadaschik, D.; Kube, D.; Baldus, S.E.; Flucke, U.; Pfister, H. Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production. J. Immunol., 2000, 165(4), 1939-1948.
[http://dx.doi.org/10.4049/jimmunol.165.4.1939] [PMID: 10925276]
[13]
Grimm, C.; Watrowski, R.; Baumühlner, K.; Natter, C.; Tong, D.; Wolf, A.; Zeillinger, R.; Leodolter, S.; Reinthaller, A.; Hefler, L. Genetic variations of interleukin-1 and -6 genes and risk of cervical intraepithelial neoplasia. Gynecol. Oncol., 2011, 121(3), 537-541.
[http://dx.doi.org/10.1016/j.ygyno.2011.02.019] [PMID: 21376376]
[14]
Paradkar, P.H.; Agashe, S.V.; Joshi, J.V.; Jagtap, S.S.; Affandi, M.Z.; Vaidya, R.A. Serum IL-6 and micrometry of pap smears in women with cervical low-grade intraepithelial lesions. Asian Pac. J. Cancer Prev., 2010, 11(4), 989-992.
[PMID: 21133612]
[15]
Wei, Q.; Zhang, B.; Li, P.; Wen, X.; Yang, J. Maslinic acid inhibits colon tumorigenesis by the AMPK-mTOR signaling pathway. J. Agric. Food Chem., 2019, 67(15), 4259-4272.
[http://dx.doi.org/10.1021/acs.jafc.9b00170] [PMID: 30913881]
[16]
Nagai, N.; Yagyu, S.; Hata, A.; Nirengi, S.; Kotani, K.; Moritani, T.; Sakane, N. Maslinic acid derived from olive fruit in combination with resistance training improves muscle mass and mobility functions in the elderly. J. Clin. Biochem. Nutr., 2019, 64(3), 224-230.
[http://dx.doi.org/10.3164/jcbn.18-104] [PMID: 31138956]
[17]
Pavel, I.Z.; Csuk, R.; Danciu, C.; Avram, S.; Baderca, F.; Cioca, A.; Moacă, E.A.; Mihali, C.V.; Pinzaru, I.; Muntean, D.M.; Dehelean, C.A. Assessment of the antiangiogenic and anti-inflammatory properties of a maslinic acid derivative and its potentiation using zinc chloride. Int. J. Mol. Sci., 2019, 20(11)E2828
[http://dx.doi.org/10.3390/ijms20112828] [PMID: 31185643]
[18]
Shimazu, K.; Fukumitsu, S.; Ishijima, T.; Toyoda, T.; Nakai, Y.; Abe, K.; Aida, K.; Okada, S.; Hino, A. The anti-arthritis effect of olive-derived maslinic acid in mice is due to its promotion of tissue formation and its anti-inflammatory effects. Mol. Nutr. Food Res., 2019, 63(3)e1800543
[http://dx.doi.org/10.1002/mnfr.201800543] [PMID: 30411492]
[19]
Rufino-Palomares, E.E.; Reyes-Zurita, F.J.; García-Salguero, L.; Mokhtari, K.; Medina, P.P.; Lupiáñez, J.A.; Peragón, J. Maslinic acid, a triterpenic anti-tumoural agent, interferes with cytoskeleton protein expression in HT29 human colon-cancer cells. J. Proteomics, 2013, 83, 15-25.
[http://dx.doi.org/10.1016/j.jprot.2013.02.031] [PMID: 23499989]
[20]
Wang, D.; Tang, S.; Zhang, Q. Maslinic acid suppresses the growth of human gastric cells by inducing apoptosis via inhibition of the Interleukin- 6 mediated Janus kinase/signal transducer and activator of transcription 3 signaling pathway. Oncol. Lett., 2017, 13(6), 4875-4881.
[http://dx.doi.org/10.3892/ol.2017.6073] [PMID: 28599489]
[21]
Wang, Y.Y.; Diao, B.Z.; Zhong, L.H.; Lu, B.L.; Cheng, Y.; Yu, L.; Zhu, L.Y. Maslinic acid protects against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice. Microb. Pathog., 2018, 119, 49-53.
[http://dx.doi.org/10.1016/j.micpath.2018.04.002] [PMID: 29627448]
[22]
Yang, Y.W.; Tsai, C.W.; Mong, M.C.; Yin, M.C. Maslinic acid protected PC12 cells differentiated by nerve growth factor against β-amyloid-induced apoptosis. J. Agric. Food Chem., 2015, 63(47), 10243-10249.
[http://dx.doi.org/10.1021/acs.jafc.5b04156] [PMID: 26477978]
[23]
Márquez Martín, A.; de la Puerta Vázquez, R.; Fernández-Arche, A.; Ruiz-Gutiérrez, V. Supressive effect of maslinic acid from pomace olive oil on oxidative stress and cytokine production in stimulated murine macrophages. Free Radic. Res., 2006, 40(3), 295-302.
[http://dx.doi.org/10.1080/10715760500467935] [PMID: 16484046]
[24]
Abdelwahab, S.I.; Abdul, A.B.; Devi, N.; Taha, M.M.; Al-zubairi, A.S.; Mohan, S.; Mariod, A.A. Regression of cervical intraepithelial neoplasia by zerumbone in female Balb/c mice prenatally exposed to diethylstilboestrol: involvement of mitochondria-regulated apoptosis. Exp. Toxicol. Pathol., 2010, 62(5), 461-469.
[http://dx.doi.org/10.1016/j.etp.2009.06.005] [PMID: 19581075]
[25]
Abdul, A.B.; Abdelwahab, S.I.; Bin Jalinas, J.; Al-Zubairi, A.S.; Taha, M.M. Combination of zerumbone and cisplatin to treat cervical intraepithelial neoplasia in female BALB/c mice. Int. J. Gynecol. Cancer, 2009, 19(6), 1004-1010.
[http://dx.doi.org/10.1111/IGC.0b013e3181a83b51] [PMID: 19820360]
[26]
Mun, K.S.; Cheah, P.L.; Baharudin, N.B.; Looi, L.M. Proliferating Cell Nuclear Antigen (PCNA) activity in hepatocellular carcinoma, benign peri-neoplastic and normal liver. Malays. J. Pathol., 2006, 28(2), 73-77.
[PMID: 18376794]
[27]
Salgado, R.; Benoy, I.; Weytjens, R.; Van Bockstaele, D.; Van Marck, E.; Huget, P.; Hoylaerts, M.; Vermeulen, P.; Dirix, L.Y. Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer. Br. J. Cancer, 2002, 87(12), 1437-1444.
[http://dx.doi.org/10.1038/sj.bjc.6600655] [PMID: 12454774]
[28]
Wei, L.H.; Kuo, M.L.; Chen, C.A.; Chou, C.H.; Lai, K.B.; Lee, C.N.; Hsieh, C.Y. Interleukin- 6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene, 2003, 22(10), 1517-1527.
[http://dx.doi.org/10.1038/sj.onc.1206226] [PMID: 12629515]
[29]
Su, J.L.; Lai, K.P.; Chen, C.A.; Yang, C.Y.; Chen, P.S.; Chang, C.C.; Chou, C.H.; Hu, C.L.; Kuo, M.L.; Hsieh, C.Y.; Wei, L.H. A novel peptide specifically binding to Interleukin- 6 receptor (gp80) inhibits angiogenesis and tumor growth. Cancer Res., 2005, 65(11), 4827-4835.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0188] [PMID: 15930303]
[30]
Ibrahim, S.; Bustamam, A.; Devi, N.; Halkim, M.N.; Al-Zubairi, A.S.; Syam, M.M. The establishment and use of an in vivo animal model for cervical intra-epithelial neoplasia. Int. J. Cancer Res., 2008, 4(3), 61-70.
[http://dx.doi.org/10.3923/ijcr.2008.61.70]
[31]
Castro, F.A.; Haimila, K.; Sareneva, I.; Schmitt, M.; Lorenzo, J.; Kunkel, N.; Kumar, R.; Försti, A.; Kjellberg, L.; Hallmans, G.; Lehtinen, M.; Hemminki, K.; Pawlita, M. Association of HLA-DRB1, Interleukin- 6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population--a candidate gene approach. Int. J. Cancer, 2009, 125(8), 1851-1858.
[http://dx.doi.org/10.1002/ijc.24529] [PMID: 19585495]
[32]
Denny, L. Cytological screening for cervical cancer prevention. Best Pract. Res. Clin. Obstet. Gynaecol., 2012, 26(2), 189-196.
[http://dx.doi.org/10.1016/j.bpobgyn.2011.08.001] [PMID: 22071306]
[33]
Bhatla, N.; Singhal, S. Primary HPV screening for cervical cancer. Best Pract. Res. Clin. Obstet. Gynaecol., 2020, 65, 98-108.
[http://dx.doi.org/10.1016/j.bpobgyn.2020.02.008] [PMID: 32291178]
[34]
Crosbie, E.J.; Einstein, M.H.; Franceschi, S.; Kitchener, H.C. Human papillomavirus and cervical cancer. Lancet, 2013, 382(9895), 889-899.
[http://dx.doi.org/10.1016/S0140-6736(13)60022-7] [PMID: 23618600]
[35]
Parra, A.; Rivas, F.; Lopez, P.E.; Garcia-Granados, A.; Martinez, A.; Albericio, F.; Marquez, N.; Muñoz, E. Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides. Bioorg. Med. Chem., 2009, 17(3), 1139-1145.
[http://dx.doi.org/10.1016/j.bmc.2008.12.041] [PMID: 19135380]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy