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

Paclitaxel Nanoparticles Induce Apoptosis and Regulate TXR1, CYP3A4 and CYP2C8 in Breast Cancer and Hepatoma Cells

Author(s): Thoria Diab, Samar S. Alkafaas, Thanaa I. Shalaby and Mohamed Hessien*

Volume 20, Issue 13, 2020

Page: [1582 - 1591] Pages: 10

DOI: 10.2174/1871520620666200504071530

Price: $65

conference banner
Abstract

Background and Objective: Although the anticancer potentials of water-insoluble drugs are improved by nanoformulation, other intervening factors may contribute in the drug efficacy. This work was designated to explore the effect of paclitaxel-loaded Poly(Lactic-co-Glycolic Acid) (PLGA) nanoparticles on the viability of cancer cells, the expression of Taxol Resistance gene I (TXR1) and paclitaxel metabolizing genes.

Methods: Paclitaxel loaded PLGA Nanoparticles (PTX-NPs) were prepared, physically characterized and used in the treatment of breast adenocarcinoma cells (MCF-7) and hepatoma cells (HepG2). Cells viability and apoptosis were investigated. In parallel, RNA was isolated, reverse transcribed and used to monitor the expression levels of TXR1, CYP 3A4 and CYP2C8 genes.

Results: PTX-NPs were characterized by transmission electron microscopy to be of a nano-size sphere-like shape. FTIR analysis revealed good coupling between PTX and PLGA. The encapsulation efficiency was 99% and the drug release demonstrated a progressive releasing phase followed by slower and sustained releasing phases. Although HepG2 cells demonstrated more resistance to PTX than MCF-7 cells, both cell types were more responsive to PTX-NPS compared to PTX. The IC50 values decreased from 19.3 to 6.7 in breast cancer cells and from 42.5 to 13.1μg/ml in hepatoma cells. The apoptosis was the key mechanism in both cells, where at least 44% of cells underwent apoptosis. The expression of TXR1 decreased when either cells were treated with PTX-NPs, respectively, meanwhile the expressions of CYP3A4 and CYP2C8 were increased.

Conclusion: Taken together, this in vitro study reports the associations between the enhanced responsiveness of MCF-7 and HepG2 cells to PLGA-loaded paclitaxel nanoparticles and the accompanying decrease in the cells resistance to the PTX and its enhanced metabolism.

Keywords: Breast cancer, paclitaxel nanoparticles, PLGA, taxol resistance gene, CYPs, apoptosis.

« Previous Next »
Graphical Abstract

[1]
Kampan, N.C.; Madondo, M.T.; McNally, O.M.; Quinn, M.; Plebanski, M. Paclitaxel and its evolving role in the management of ovarian cancer. BioMed Res. Int., 2015, 2015 413076
[http://dx.doi.org/10.1155/2015/413076] [PMID: 26137480]
[2]
Symmans, W.F.; Volm, M.D.; Shapiro, R.L.; Perkins, A.B.; Kim, A.Y.; Demaria, S.; Yee, H.T.; McMullen, H.; Oratz, R.; Klein, P.; Formenti, S.C.; Muggia, F. Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration: Implications for early prediction of breast cancer response to neoadjuvant treatment. Clin. Cancer Res., 2000, 6(12), 4610-4617.
[PMID: 11156210]
[3]
Wang, H.; Li, M.; Rinehart, J.J.; Zhang, R. Dexamethasone as a chemoprotectant in cancer chemotherapy: Hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine. Cancer Chemother. Pharmacol., 2004, 53(6), 459-467.
[http://dx.doi.org/10.1007/s00280-003-0759-9] [PMID: 14752578]
[4]
Holmes, F.A.; Walters, R.S.; Theriault, R.L.; Forman, A.D.; Newton, L.K.; Raber, M.N.; Buzdar, A.U.; Frye, D.K.; Hortobagyi, G.N. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J. Natl. Cancer Inst., 1991, 83(24), 1797-1805.
[http://dx.doi.org/10.1093/jnci/83.24.1797-a] [PMID: 1683908]
[5]
Ibrahim, N.K.; Desai, N.; Legha, S.; Soon-Shiong, P.; Theriault, R.L.; Rivera, E.; Esmaeli, B.; Ring, S.E.; Bedikian, A.; Hortobagyi, G.N.; Ellerhorst, J.A. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin. Cancer Res., 2002, 8(5), 1038-1044.
[PMID: 12006516]
[6]
Kratz, F. Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles. J. Control. Release, 2008, 132(3), 171-183.
[http://dx.doi.org/10.1016/j.jconrel.2008.05.010] [PMID: 18582981]
[7]
Gradishar, W.J.; Tjulandin, S.; Davidson, N.; Shaw, H.; Desai, N.; Bhar, P.; Hawkins, M.; O’Shaughnessy, J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol., 2005, 23(31), 7794-7803.
[http://dx.doi.org/10.1200/JCO.2005.04.937] [PMID: 16172456]
[8]
Fonseca, C.; Simões, S.; Gaspar, R. Paclitaxel-loaded PLGA nanoparticles: Preparation, physicochemical characterization and in vitro anti-tumoral activity. J. Control. Release, 2002, 83(2), 273-286.
[http://dx.doi.org/10.1016/S0168-3659(02)00212-2] [PMID: 12363453]
[9]
Gu, Q.; Xing, J.Z.; Huang, M.; He, C.; Chen, J. SN-38 loaded polymeric micelles to enhance cancer therapy. Nanotechnology, 2012, 23(20) 205101
[http://dx.doi.org/10.1088/0957-4484/23/20/205101] [PMID: 22543761]
[10]
Xu, X.; Wang, L.; Xu, H.Q.; Huang, X.E.; Qian, Y.D.; Xiang, J. Clinical comparison between paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac. J. Cancer Prev., 2013, 14(4), 2591-2594.
[http://dx.doi.org/10.7314/APJCP.2013.14.4.2591] [PMID: 23725180]
[11]
Wu, C.; Gao, Y.; Liu, Y.; Xu, X. Pure paclitaxel nanoparticles: Preparation, characterization, and antitumor effect for human liver cancer SMMC-7721 cells. Int. J. Nanomedicine, 2018, 13, 6189-6198.
[http://dx.doi.org/10.2147/IJN.S169209] [PMID: 30349243]
[12]
Chung, H.J.; Kim, H.J.; Hong, S.T. Tumor-specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment. Nanomedicine (Lond.), 2019, 23 102089
[PMID: 31487550]
[13]
Liebmann, J.E.; Cook, J.A.; Lipschultz, C.; Teague, D.; Fisher, J.; Mitchell, J.B. Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines. Br. J. Cancer, 1993, 68(6), 1104-1109.
[http://dx.doi.org/10.1038/bjc.1993.488] [PMID: 7903152]
[14]
Saunders, D.E.; Lawrence, W.D.; Christensen, C.; Wappler, N.L.; Ruan, H.; Deppe, G. Paclitaxel-induced apoptosis in MCF-7 breast-cancer cells. Int. J. Cancer, 1997, 70(2), 214-220.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19970117)70:2<214: AID-IJC13>3.0.CO;2-I] [PMID: 9009163]
[15]
Vicari, L.; Musumeci, T.; Giannone, I.; Adamo, L.; Conticello, C.; De Maria, R.; Pignatello, R.; Puglisi, G.; Gulisano, M. Paclitaxel loading in PLGA nanospheres affected the in vitro drug cell accumulation and antiproliferative activity. BMC Cancer, 2008, 8(1), 212.
[http://dx.doi.org/10.1186/1471-2407-8-212] [PMID: 18657273]
[16]
Fransson, M.N.; Gréen, H.; Litton, J.E.; Friberg, L.E. Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model. Drug Metab. Dispos., 2011, 39(2), 247-255.
[http://dx.doi.org/10.1124/dmd.110.035394] [PMID: 21056987]
[17]
Bai, Z.; Zhang, Z.; Qu, X.; Han, W.; Ma, X. Sensitization of breast cancer cells to taxol by inhibition of taxol resistance gene 1. Oncol. Lett., 2012, 3(1), 135-140.
[http://dx.doi.org/10.3892/ol.2011.416] [PMID: 22740869]
[18]
Du, H.; Yang, W.; Chen, L.; Shi, M.; Seewoo, V.; Wang, J.; Lin, A.; Liu, Z.; Qiu, W. Role of autophagy in resistance to oxaliplatin in hepatocellular carcinoma cells. Oncol. Rep., 2012, 27(1), 143-150.
[PMID: 21935576]
[19]
Madani, F.; Esnaashari, S.S.; Mujokoro, B.; Dorkoosh, F.; Khosravani, M.; Adabi, M. Investigation of effective parameters on size of paclitaxel loaded PLGA nanoparticles. Adv. Pharm. Bull., 2018, 8(1), 77-84.
[http://dx.doi.org/10.15171/apb.2018.010] [PMID: 29670842]
[20]
Devi, T.; Devi, T.R.; Gayathri, S. FTIR and FT-Raman spectral analysis of paclitaxel drugs. Int. J. Pharm. Sci. Rev. Res., 2010, 2(2), 106-110.
[21]
Stinchcombe, T.E. Nanoparticle albumin-bound paclitaxel: A novel Cremphor-EL-free formulation of paclitaxel. Nanomedicine (Lond.), 2007, 2(4), 415-423.
[http://dx.doi.org/10.2217/17435889.2.4.415] [PMID: 17716129]
[22]
Gu, Q.; Xing, J.Z.; Huang, M.; Zhang, X.; Chen, J. Nanoformulation of paclitaxel to enhance cancer therapy. J. Biomater. Appl., 2013, 28(2), 298-307.
[http://dx.doi.org/10.1177/0885328212446822] [PMID: 22561979]
[23]
Monteiro, L.O.F.; Malachias, Â.; Pound-Lana, G.; Magalhães-Paniago, R.; Mosqueira, V.C.F.; Oliveira, M.C.; de Barros, A.L.B.; Leite, E.A. Paclitaxel-loaded pH-sensitive liposome: New insights on structural and physicochemical characterization. Langmuir, 2018, 34(20), 5728-5737.
[http://dx.doi.org/10.1021/acs.langmuir.8b00411] [PMID: 29676924]
[24]
Danhier, F.; Lecouturier, N.; Vroman, B.; Jérôme, C.; Marchand-Brynaert, J.; Feron, O.; Préat, V. Paclitaxel-loaded PEGylated PLGA-based nanoparticles: In vitro and in vivo evaluation. J. Control. Release, 2009, 133(1), 11-17.
[http://dx.doi.org/10.1016/j.jconrel.2008.09.086] [PMID: 18950666]
[25]
Maeda, H. Macromolecular therapeutics in cancer treatment: The EPR effect and beyond. J. Control. Release, 2012, 164(2), 138-144.
[http://dx.doi.org/10.1016/j.jconrel.2012.04.038] [PMID: 22595146]
[26]
Nicolete, R.; dos Santos, D.F.; Faccioli, L.H. The uptake of PLGA micro or nanoparticles by macrophages provokes distinct in vitro inflammatory response. Int. Immunopharmacol., 2011, 11(10), 1557-1563.
[http://dx.doi.org/10.1016/j.intimp.2011.05.014] [PMID: 21621649]
[27]
Mora-Huertas, C.E.; Fessi, H.; Elaissari, A. Polymer-based nanocapsules for drug delivery. Int. J. Pharm., 2010, 385(1-2), 113-142.
[http://dx.doi.org/10.1016/j.ijpharm.2009.10.018] [PMID: 19825408]
[28]
Zhang, B.; Sai Lung, P.; Zhao, S.; Chu, Z.; Chrzanowski, W.; Li, Q. Shape dependent cytotoxicity of PLGA-PEG nanoparticles on human cells. Sci. Rep., 2017, 7(1), 7315.
[http://dx.doi.org/10.1038/s41598-017-07588-9] [PMID: 28779154]
[29]
Xiong, S.; George, S.; Yu, H.; Damoiseaux, R.; France, B.; Ng, K.W.; Loo, J.S. Size influences the cytotoxicity of Poly (Lactic-co-Glycolic Acid) (PLGA) and titanium dioxide (TiO2) nanoparticles. Arch. Toxicol., 2013, 87(6), 1075-1086.
[http://dx.doi.org/10.1007/s00204-012-0938-8] [PMID: 22983807]
[30]
Yadav, D.; Anwar, M.F.; Garg, V.; Kardam, H.; Beg, M.N.; Suri, S.; Gaur, S.; Asif, M. Development of polymeric nanopaclitaxel and comparison with free paclitaxel for effects on cell proliferation of MCF-7 and B16F0 carcinoma cells. Asian Pac. J. Cancer Prev., 2014, 15(5), 2335-2340.
[http://dx.doi.org/10.7314/APJCP.2014.15.5.2335] [PMID: 24716980]
[31]
Lin, Y-H.; Chen, B.Y.H.; Lai, W.T.; Wu, S.F.; Guh, J.H.; Cheng, A.L.; Hsu, L.C. The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells. Naunyn Schmiedebergs Arch. Pharmacol., 2015, 388(1), 19-31.
[http://dx.doi.org/10.1007/s00210-014-1032-y] [PMID: 25164962]
[32]
Alkafaas, S.S.; Diab, T.; Shalaby, T.; Hessien, M. Dexamethasone impoves the responsiveness of hepatoma cell for both free and solvent containing paclitaxel in vitro. Egypt. J. Biochem. Mol. Biol., 2019, 37(1&2), 95-110.
[33]
Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release, 2012, 161(2), 505-522.
[http://dx.doi.org/10.1016/j.jconrel.2012.01.043] [PMID: 22353619]
[34]
Bhalla, K.; Ibrado, A.M.; Tourkina, E.; Tang, C.; Mahoney, M.E.; Huang, Y. Taxol induces internucleosomal DNA fragmentation associated with programmed cell death in human myeloid leukemia cells. Leukemia, 1993, 7(4), 563-568.
[PMID: 8096557]
[35]
Donaldson, K.L.; Goolsby, G.L.; Wahl, A.F. Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle. Int. J. Cancer, 1994, 57(6), 847-855.
[http://dx.doi.org/10.1002/ijc.2910570614] [PMID: 7911457]
[36]
Okano, J.; Nagahara, T.; Matsumoto, K.; Murawaki, Y. The growth inhibition of liver cancer cells by paclitaxel and the involvement of extracellular signal-regulated kinase and apoptosis. Oncol. Rep., 2007, 17(5), 1195-1200.
[http://dx.doi.org/10.3892/or.17.5.1195] [PMID: 17390065]
[37]
Ben-Hamo, R.; Zilberberg, A.; Cohen, H.; Bahar-Shany, K.; Wachtel, C.; Korach, J.; Aviel-Ronen, S.; Barshack, I.; Barash, D.; Levanon, K.; Efroni, S. Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types. NPJ Precis Oncol., 2019, 23, 3-12.
[http://dx.doi.org/10.1038/s41698-019-0084-3]
[38]
Kawauchi, S.; Nakamura, T.; Miki, I.; Inoue, J.; Hamaguchi, T.; Tanahashi, T.; Mizuno, S. Downregulation of CYP3A and P-glycoprotein in the secondary inflammatory response of mice with dextran sulfate sodium-induced colitis and its contribution to cyclosporine A blood concentrations. J. Pharmacol. Sci., 2014, 124(2), 180-191.
[http://dx.doi.org/10.1254/jphs.13141FP] [PMID: 24492412]
[39]
van Eijk, M.; Boosman, R.J.; Schinkel, A.H.; Huitema, A.D.R.; Beijnen, J.H. Cytochrome P450 3A4, 3A5, and 2C8 expression in breast, prostate, lung, endometrial, and ovarian tumors: Relevance for resistance to taxanes. Cancer Chemother. Pharmacol., 2019, 84(3), 487-499.
[http://dx.doi.org/10.1007/s00280-019-03905-3] [PMID: 31309254]
[40]
Chi, H.M.; Du, J.D.; Cheng, J.; Mao, H.D. Taxol-resistant gene 1 (Txr1) mediates oxaliplatin resistance by inducing autophagy in human nasopharyngeal carcinoma cells. Med. Sci. Monit., 2019, 25, 475-483.
[http://dx.doi.org/10.12659/MSM.913180] [PMID: 30650069]

Rights & Permissions Print Cite
Article Metrics
37
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy