Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Antitumor Activity of Zinc Nanoparticles Synthesized with Berberine on Human Epithelial Colorectal Adenocarcinoma (Caco-2) Cells through Acting on Cox-2/NF-kB and p53 Pathways

Author(s): Mohamed S. Othman *, Amal H. Al-Bagawi, Sofian T. Obeidat, Mohamed A. Fareid, Ola A. Habotta and Ahmed E. Abdel Moneim

Volume 22, Issue 10, 2022

Published on: 10 January, 2022

Page: [2002 - 2010] Pages: 9

DOI: 10.2174/1871520621666211004115839

Price: $65

Abstract

Background: Drawbacks and side effects of currently available therapies to colorectal cancer (CRC) have compelled researchers to search for new therapeutic strategies.

Objective: This study was designed to investigate the effects of zinc nanoparticles biosynthesized with berberine (ZnNPs-BER) on Caco-2 cells compared to 5-Fluorouracil (5-FU) and explore the possible underlying pathways.

Methods: Caco-2 and Vero cells were treated with 5-FU, BER, or ZnNPs-BER for 24 h. Cell viability was measured by MTT assay. Oxidative stress and apoptotic markers and cell cycle were determined. Additionally, Cox-2 and NF-kB levels were also measured.

Results: The IC50 values of 5-FU, BER, and ZnNPs-BER on Caco-2 cells were found to be 34.65 μM, 19.86 μg/ml and 10.49 μg/ml, respectively by MTT assay. The IC50 value for 5-FU in Vero cells was 21.7 μg/ml, however, BER and BER-ZnNPs treatment showed non-toxic effects on the Vero cells. Further, ZnNPs-BER exerted significant induction of ROS besides exhaustion of the antioxidant capacity of tumor cells indicated by a decline in GSH and elevated NO and MDA contents. Marked increments in levels of Bax and caspase-3 were detected together with declines in Bcl- 2 levels in Caco-2 cells subjected to BER-ZnNPs therapy. On the molecular basis, upregulation in mRNA levels of pro-apoptotic genes (Bax, caspase-3, and tumor suppressor gene p53) along with downregulation in the anti-apoptotic gene (Bcl-2) were observed in ZnNPs-BER treated Caco-2 cells. Furthermore, ZnNPs-BER showed more pronounced effects on apoptosis increased cell percentage in the S and subG1 phases. In addition, green synthesis of ZnNPs with BER showed notable induction of Cox2 and NF-kB in Caco-2 cells.

Conclusion: Therefore, the antitumor potential of ZnNPs-BER in colon cancer cells may be endorsed for induction of oxidative stress, inflammation, and apoptotic changes in tumor cells. Our study documents the therapeutic potential of Zn nanoparticles conjugated with BER, which may be a new option for combined chemotherapy.

Keywords: Zinc nanoparticles, berberine, colorectal cancer, p53, Cox-2, NF-kB.

« Previous Next »
Graphical Abstract

[1]
Huang, C.; Tao, L.; Wang, X.L.; Pang, Z. Berberine reversed the epithelial-mesenchymal transition of normal colonic epithelial cells induced by SW480 cells through regulating the important components in the TGF-β pathway. J. Cell. Physiol., 2019, 234(7), 11679-11691.
[http://dx.doi.org/10.1002/jcp.27835] [PMID: 30536375]
[2]
Li, W.; Hua, B.; Saud, S.M.; Lin, H.; Hou, W.; Matter, M.S.; Jia, L.; Colburn, N.H.; Young, M.R. Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol. Carcinog., 2015, 54(10), 1096-1109.
[http://dx.doi.org/10.1002/mc.22179] [PMID: 24838344]
[3]
Wei, J.; Yu, W.; Hao, R.; Fan, J.; Gao, J. Anthocyanins from aronia melanocarpa induce apoptosis in Caco-2 cells through Wnt/β-catenin signaling pathway. Chem. Biodivers., 2020, 17(11) ,e2000654
[http://dx.doi.org/10.1002/cbdv.202000654] [PMID: 33016000]
[4]
Liu, X.; Ji, Q.; Ye, N.; Sui, H.; Zhou, L.; Zhu, H.; Fan, Z.; Cai, J.; Li, Q. Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE 2 mediated JAK2/STAT3 signaling pathway. PLoS One, 2015, 10(5) ,e0123478
[http://dx.doi.org/10.1371/journal.pone.0123478] [PMID: 25954974]
[5]
Aalami, A.H.; Mesgari, M.; Sahebkar, A. synthesis and characterization of green zinc oxide nanoparticles with antiproliferative effects through apoptosis induction and MicroRNA modulation in breast cancer cells. Bioinorg. Chem. Appl., 2020, 2020 ,8817110
[http://dx.doi.org/10.1155/2020/8817110] [PMID: 33273900]
[6]
Jiang, J.; Pi, J.; Cai, J. The advancing of zinc oxide nanoparticles for biomedical applications. Bioinorg. Chem. Appl., 2018, 2018 ,1062562
[http://dx.doi.org/10.1155/2018/1062562] [PMID: 30073019]
[7]
Ezhuthupurakkal, P.B.; Ariraman, S.; Arumugam, S.; Subramaniyan, N.; Muthuvel, S.K.; Kumpati, P.; Rajamani, B.; Chinnasamy, T. Anticancer potential of ZnO nanoparticle-ferulic acid conjugate on Huh-7 and HepG2 cells and diethyl nitrosamine induced hepatocellular cancer on Wistar albino rat. Nanomedicine, 2018, 14(2), 415-428.
[http://dx.doi.org/10.1016/j.nano.2017.11.003] [PMID: 29166623]
[8]
Akhtar, M.J.; Ahamed, M.; Kumar, S.; Khan, M.M.; Ahmad, J.; Alrokayan, S.A. Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species. Int. J. Nanomedicine, 2012, 7, 845-857.
[PMID: 22393286]
[9]
El-Shorbagy, H.M.; Eissa, S.M.; Sabet, S.; El-Ghor, A.A. Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice. Int. J. Nanomedicine, 2019, 14, 3911-3928.
[http://dx.doi.org/10.2147/IJN.S204757] [PMID: 31213808]
[10]
Rajeshkumar, S.; Kumar, S.V.; Ramaiah, A.; Agarwal, H.; Lakshmi, T.; Roopan, S.M. Biosynthesis of zinc oxide nanoparticles usingMangifera indica leaves and evaluation of their antioxidant and cytotoxic properties in lung cancer (A549) cells. Enzyme Microb. Technol., 2018, 117, 91-95.
[http://dx.doi.org/10.1016/j.enzmictec.2018.06.009] [PMID: 30037558]
[11]
Umar, H.; Kavaz, D.; Rizaner, N. Biosynthesis of zinc oxide nanoparticles using Albizia lebbeck stem bark, and evaluation of its antimicrobial, antioxidant, and cytotoxic activities on human breast cancer cell lines. Int. J. Nanomedicine, 2018, 14, 87-100.
[http://dx.doi.org/10.2147/IJN.S186888] [PMID: 30587987]
[12]
Wang, L.; Liu, L.; Shi, Y.; Cao, H.; Chaturvedi, R.; Calcutt, M.W.; Hu, T.; Ren, X.; Wilson, K.T.; Polk, D.B.; Yan, F. Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor. PLoS One, 2012, 7(5) ,e36418
[http://dx.doi.org/10.1371/journal.pone.0036418] [PMID: 22574158]
[13]
Jia, L.; Xue, K.; Liu, J.; Habotta, O.A.; Hu, L.; Abdel Moneim, A.E. Anticolitic effect of berberine in rat experimental model: Impact of PGE2/p38 MAPK pathways. Mediators Inflamm., 2020, 2020 ,9419085
[http://dx.doi.org/10.1155/2020/9419085] [PMID: 33061833]
[14]
Palmieri, A.; Scapoli, L.; Iapichino, A.; Mercolini, L.; Mandrone, M.; Poli, F.; Giannì, A.B.; Baserga, C.; Martinelli, M. Berberine and Tinospora cordifolia exert a potential anticancer effect on colon cancer cells by acting on specific pathways. Int. J. Immunopathol. Pharmacol., 2019, 33 ,2058738419855567
[http://dx.doi.org/10.1177/2058738419855567] [PMID: 31663444]
[15]
Wang, Y.; Liu, Y.; Du, X.; Ma, H.; Yao, J. The anti-cancer mechanisms of berberine: a review. Cancer Manag. Res., 2020, 12, 695-702.
[http://dx.doi.org/10.2147/CMAR.S242329] [PMID: 32099466]
[16]
Liu, Y.; Hua, W.; Li, Y.; Xian, X.; Zhao, Z.; Liu, C.; Zou, J.; Li, J.; Fang, X.; Zhu, Y. Berberine suppresses colon cancer cell proliferation by inhibiting the SCAP/SREBP-1 signaling pathway-mediated lipogenesis. Biochem. Pharmacol., 2020, 174 ,113776
[http://dx.doi.org/10.1016/j.bcp.2019.113776] [PMID: 31874145]
[17]
Kim, S.; Han, J.; Kim, N.Y.; Lee, S.K.; Cho, D.H.; Choi, M.Y.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Nam, S.J.; Lee, J.E. Effect of berberine on p53 expression by TPA in breast cancer cells. Oncol. Rep., 2012, 27(1), 210-215.
[PMID: 21964832]
[18]
Wang, H.Y.; Yu, H.Z.; Huang, S.M.; Zheng, Y.L. p53, Bcl-2 and cox-2 are involved in berberine hydrochloride-induced apoptosis of HeLa229 cells. Mol. Med. Rep., 2016, 14(4), 3855-3861.
[http://dx.doi.org/10.3892/mmr.2016.5696] [PMID: 27601129]
[19]
Samad, M.A.; Saiman, M.Z.; Abdul Majid, N.; Karsani, S.A.; Yaacob, J.S. Berberine inhibits telomerase activity and induces cell cycle arrest and telomere erosion in colorectal cancer cell line, HCT 116. Molecules, 2021, 26(2), 376.
[http://dx.doi.org/10.3390/molecules26020376] [PMID: 33450878]
[20]
Nagendraprabhu, P.; Sudhandiran, G. Astaxanthin inhibits tumor invasion by decreasing extracellular matrix production and induces apoptosis in experimental rat colon carcinogenesis by modulating the expressions of ERK-2, NFkB and COX-2. Invest. New Drugs, 2011, 29(2), 207-224.
[http://dx.doi.org/10.1007/s10637-009-9342-5] [PMID: 19876598]
[21]
Tang, T.C.; Poon, R.T.; Lau, C.P.; Xie, D.; Fan, S.T. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma. World J. Gastroenterol., 2005, 11(13), 1896-1902.
[http://dx.doi.org/10.3748/wjg.v11.i13.1896] [PMID: 15800977]
[22]
Kim, H.S.; Sharma, A.; Ren, W.X.; Han, J.; Kim, J.S. COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. Biomaterials, 2018, 185, 63-72.
[http://dx.doi.org/10.1016/j.biomaterials.2018.09.006] [PMID: 30223141]
[23]
Desai, S.J.; Prickril, B.; Rasooly, A. Mechanisms of phytonutrient modulation of cyclooxygenase-2 (COX-2) and inflammation related to cancer. Nutr. Cancer, 2018, 70(3), 350-375.
[http://dx.doi.org/10.1080/01635581.2018.1446091] [PMID: 29578814]
[24]
Tolosa, L.; Donato, M.T.; Gómez-Lechón, M.J. General cytotoxicity assessment by means of the MTT assay. Methods Mol. Biol., 2015, 1250, 333-348.
[http://dx.doi.org/10.1007/978-1-4939-2074-7_26] [PMID: 26272156]
[25]
Wang, X.; Roper, M.G. Measurement of DCF fluorescence as a measure of reactive oxygen species in murine islets of Langerhans. Anal. Methods, 2014, 6(9), 3019-3024.
[http://dx.doi.org/10.1039/C4AY00288A] [PMID: 24955137]
[26]
Ellman, G.L. Tissue sulfhydryl groups. Arch. Biochem. Biophys., 1959, 82(1), 70-77.
[http://dx.doi.org/10.1016/0003-9861(59)90090-6] [PMID: 13650640]
[27]
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[28]
El-Garawani, I.M.; El-Nabi, S.H.; Dawoud, G.T.; Esmail, S.M.; Abdel Moneim, A.E. Triggering of apoptosis and cell cycle arrest by fennel and clove oils in Caco-2 cells: the role of combination. Toxicol. Mech. Methods, 2019, 29(9), 710-722.
[http://dx.doi.org/10.1080/15376516.2019.1650149] [PMID: 31364915]
[29]
Vuddanda, P.R.; Rajamanickam, V.M.; Yaspal, M.; Singh, S. Investigations on agglomeration and haemocompatibility of vitamin E TPGS surface modified berberine chloride nanoparticles. BioMed Res. Int., 2014, 2014 ,951942
[http://dx.doi.org/10.1155/2014/951942] [PMID: 25162037]
[30]
Li, G.; Zhang, C.; Liang, W.; Zhang, Y.; Shen, Y.; Tian, X. Berberine regulates the Notch1/PTEN/PI3K/AKT/mTOR pathway and acts synergistically with 17-AAG and SAHA in SW480 colon cancer cells. Pharm. Biol., 2021, 59(1), 21-30.
[http://dx.doi.org/10.1080/13880209.2020.1865407] [PMID: 33417512]
[31]
Hao, X.; Yao, A.; Gong, J.; Zhu, W.; Li, N.; Li, J. Berberine ameliorates pro-inflammatory cytokine-induced endoplasmic reticulum stress in human intestinal epithelial cells in vitro. Inflammation, 2012, 35(3), 841-849.
[http://dx.doi.org/10.1007/s10753-011-9385-6] [PMID: 21922249]
[32]
Kim, S.; Lee, S.Y.; Cho, H-J. Berberine and zinc oxide-based nanoparticles for the chemo-photothermal therapy of lung adenocarcinoma. Biochem. Biophys. Res. Commun., 2018, 501(3), 765-770.
[http://dx.doi.org/10.1016/j.bbrc.2018.05.063] [PMID: 29758197]
[33]
Anitha, R.; Ramesh, K.; Ravishankar, T.; Kumar, K.S.; Ramakrishnappa, T. Cytotoxicity, antibacterial and antifungal activities of ZnO nanoparticles prepared by the Artocarpus gomezianus fruit mediated facile green combustion method. J. Sci.: Adv. Materi. Dev., 2018, 3, 440-451.
[34]
Song, Y.; Guan, R.; Lyu, F.; Kang, T.; Wu, Y.; Chen, X. In vitro cytotoxicity of silver nanoparticles and zinc oxide nanoparticles to human epithelial colorectal adenocarcinoma (Caco-2) cells. Mutat. Res. Fundam. Mol. Mech. Mutagen., 2014, 769, 113-118.
[http://dx.doi.org/10.1016/j.mrfmmm.2014.08.001] [PMID: 25771730]
[35]
Lee, K.; Lee, H.; Lee, K.W.; Park, T.G. Optical imaging of intracellular reactive oxygen species for the assessment of the cytotoxicity of nanoparticles. Biomaterials, 2011, 32(10), 2556-2565.
[http://dx.doi.org/10.1016/j.biomaterials.2010.11.072] [PMID: 21247630]
[36]
Skonieczna, M.; Hudy, D.; Poterala-Hejmo, A.; Hejmo, T.; Buldak, R.J.; Dziedzic, A. Effects of resveratrol, berberine and their combinations on reactive oxygen species, survival and apoptosis in human squamous carcinoma (SCC-25) cells. Anticancer. Agents Med. Chem., 2019, 19(9), 1161-1171.
[http://dx.doi.org/10.2174/1871520619666190405111151] [PMID: 30950357]
[37]
Li, Z.; Liu, Y.; Wang, F.; Gao, Z.; Elhefny, M.A.; Habotta, O.A.; Abdel Moneim, A.E.; Kassab, R.B. Neuroprotective effects of protocatechuic acid on sodium arsenate induced toxicity in mice: Role of oxidative stress, inflammation, and apoptosis. Chem. Biol. Interact., 2021, 337 ,109392
[http://dx.doi.org/10.1016/j.cbi.2021.109392] [PMID: 33497687]
[38]
Tang, Q.; Xia, H.; Liang, W.; Huo, X.; Wei, X. Synthesis and characterization of zinc oxide nanoparticles from Morus nigra and its anticancer activity of AGS gastric cancer cells. J. Photochem. Photobiol. B, 2020, 202 ,111698
[http://dx.doi.org/10.1016/j.jphotobiol.2019.111698] [PMID: 31734436]
[39]
Raja, S.B.; Rajendiran, V.; Kasinathan, N.K. P, A.; Venkatabalasubramanian, S.; Murali, M. R.; Devaraj, H.; Devaraj, S. N. Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression Food and Chem. Toxicol.: Int. J. Pub. British Indust. Biol. Res. Associ., 2017, 106, 92-106.
[40]
Wu, F.; Chen, Y.; Li, G.; Zhu, D.; Wang, L.; Wang, J. Zinc oxide nanoparticles synthesized from Allium cepa prevents UVB radiation mediated inflammation in human epidermal keratinocytes (HaCaT cells). Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 3548-3558.
[http://dx.doi.org/10.1080/21691401.2019.1642905] [PMID: 31456420]
[41]
Wang, Y.; Zhou, M.; Shang, D. Berberine inhibits human gastric cancer cell growth via deactivation of p38/JNK pathway, induction of mitochondrial-mediated apoptosis, caspase activation and NF-κB inhibition J. B.U.ON. Offici. J. Balkan Union Oncol., 2020, 25, 314-318.
[42]
L, S. W.; Lee, C. H.; Lin, M. S.; Chi, C. W.; Chen, Y. J.; Wang, G. S.; Liao, K. W.; Chiu, L. P.; Wu, S. H.; Huang, D. M.; Chen, L.; Shen, Y. S. ZnO nanoparticles induced caspase-dependent apoptosis in gingival squamous cell carcinoma through mitochondrial dysfunction and p70S6K signaling pathway. Int. J. Mol. Sci., 2020, 21(5), 1612.
[43]
Sharma, V.; Anderson, D.; Dhawan, A. Zinc oxide nanoparticles induce oxidative stress and genotoxicity in human liver cells (HepG2). J. Biomed. Nanotechnol., 2011, 7(1), 98-99.
[http://dx.doi.org/10.1166/jbn.2011.1220] [PMID: 21485822]
[44]
Pandurangan, M.; Enkhtaivan, G.; Kim, D.H. Anticancer studies of synthesized ZnO nanoparticles against human cervical carcinoma cells. J. Photochem. Photobiol. B, 2016, 158, 206-211.
[http://dx.doi.org/10.1016/j.jphotobiol.2016.03.002] [PMID: 26985734]
[45]
Bai Aswathanarayan, J.; Rai Vittal, R.; Muddegowda, U. Anticancer activity of metal nanoparticles and their peptide conjugates against human colon adenorectal carcinoma cells. Artif. Cells Nanomed. Biotechnol., 2018, 46(7), 1444-1451.
[http://dx.doi.org/10.1080/21691401.2017.1373655] [PMID: 28884587]
[46]
Ma, W.; Zhang, Y.; Yu, M.; Wang, B.; Xu, S.; Zhang, J.; Li, X.; Ye, X. In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. Int. Immunopharmacol., 2020, 87 ,106787
[http://dx.doi.org/10.1016/j.intimp.2020.106787] [PMID: 32707493]
[47]
Bai, D.P.; Zhang, X.F.; Zhang, G.L.; Huang, Y.F.; Gurunathan, S. Zinc oxide nanoparticles induce apoptosis and autophagy in human ovarian cancer cells. Int. J. Nanomedicine, 2017, 12, 6521-6535.
[http://dx.doi.org/10.2147/IJN.S140071] [PMID: 28919752]
[48]
Ng, C.T.; Yong, L.Q.; Hande, M.P.; Ong, C.N.; Yu, L.E.; Bay, B.H.; Baeg, G.H. Zinc oxide nanoparticles exhibit cytotoxicity and genotoxicity through oxidative stress responses in human lung fibroblasts and Drosophila melanogaster. Int. J. Nanomedicine, 2017, 12, 1621-1637.
[http://dx.doi.org/10.2147/IJN.S124403] [PMID: 28280330]
[49]
Son, Y.; An, Y.; Jung, J.; Shin, S.; Park, I.; Gwak, J.; Ju, B.G.; Chung, Y.H.; Na, M.; Oh, S. Protopine isolated from Nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53. Phytother. Res., 2019, 33(6), 1689-1696.
[http://dx.doi.org/10.1002/ptr.6357] [PMID: 30932278]
[50]
Jiménez, S.; Gascón, S.; Luquin, A.; Laguna, M.; Ancin-Azpilicueta, C.; Rodríguez-Yoldi, M.J. Rosa canina extracts have antiproliferative and antioxidant effects on Caco-2 human colon cancer. PLoS One, 2016, 11(7) ,e0159136
[http://dx.doi.org/10.1371/journal.pone.0159136] [PMID: 27467555]
[51]
Fernandez-Gil, B.I.; Guerra-Librero, A.; Shen, Y.Q.; Florido, J.; Martínez-Ruiz, L.; García-López, S.; Adan, C.; Rodríguez-Santana, C.; Acuña-Castroviejo, D.; Quiñones-Hinojosa, A.; Fernández-Martínez, J.; Abdel Moneim, A.E.; López, L.C.; Rodríguez Ferrer, J.M.; Escames, G. 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
[http://dx.doi.org/10.1155/2019/7187128] [PMID: 30944696]
[52]
Boroumand Moghaddam, A.; Moniri, M.; Azizi, S.; Abdul Rahim, R.; Bin Ariff, A.; Navaderi, M.; Mohamad, R. Eco-friendly formulated zinc oxide nanoparticles: Induction of cell cycle arrest and apoptosis in the MCF-7 cancer cell line. Genes (Basel), 2017, 8(10), 8.
[http://dx.doi.org/10.3390/genes8100281] [PMID: 29053567]
[53]
Jain, A.K.; Singh, D.; Dubey, K.; Maurya, R.; Pandey, A.K. Zinc oxide nanoparticles induced gene mutation at the HGPRT locus and cell cycle arrest associated with apoptosis in V-79 cells. J. Appl. Toxicol.,. 2019, 39(5), 735-750.
[http://dx.doi.org/10.1002/jat.3763] [PMID: 30618096]

Rights & Permissions Print Cite
Article Metrics
31
1
© 2024 Bentham Science Publishers | Privacy Policy