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

Characterization of Cepharanthin Nanosuspensions and Evaluation of Their In Vitro Activity for the HepG2 Hepatocellular Carcinoma Cell Line

Author(s): Yue Zhao, Tingting Fu, Gaoke Meng, Fangxia Qiao, Yanhui Hou, Yanhua Liu and Jianhong Yang*

Volume 20, Issue 18, 2020

Page: [2293 - 2303] Pages: 11

DOI: 10.2174/1871520620999200730170844

Price: $65

Abstract

Background: Conventional cancer therapeutics has enormous toxicity and severe side effects that generate multi-drug resistance. Therefore, an urgent need exists for new alternative therapeutic agents for cancer treatment. Cepharanthin (CEP) has anti-cancer potential but has poor aqueous solubility, which limits its clinical use. Nanosuspensions (NS) are attractive as insoluble drug delivery systems.

Objectives: In this study, we used D-alpha Tocopherol acid Polyethylene Glycol Succinate (TPGS), Polyvinylpyrrolidone (PVP) VA64, and Croscamellose Sodium (CCS) as stabilizers to produce TPGS-CEP-NS, PVP VA64-CEP-NS, and CCS-CEP-NS by wet-milling technology, and then characterized the NS and evaluated their functional activities in vitro.

Methods: CEP Nanosuspensions (CEP-NS) were prepared by the wet-milling method. The prepared NS were characterized by particle size distribution, zeta potential, morphology, surface properties, and molecular interactions. The NS were evaluated for their effects on HepG2 cells in vitro. The evaluations included assessment of cellular cytotoxicity, cellular apoptosis, NS uptake by cells, and mitochondrial membrane potential changes.

Results: CEP-NS showed an appropriate particle size and were physically stable. All CEP-NS exhibited HepG2 enhanced anti-proliferative effects by reducing cell viability, enhanced cellular uptake, induced cellular apoptosis, and mitochondrial membrane potential loss.

Conclusions: CEP-NS may be effective therapeutic agents for the treatment of hepatocellular carcinoma.

Keywords: Nanosuspension, cepharanthin, stabilizers, anti-cancer, hepatocellular carcinoma, HEPG2.

« Previous Next »
Graphical Abstract

[1]
Li, Y.; Wu, Z.; He, W.; Qin, C.; Yao, J.; Zhou, J.; Yin, L. Globular protein-coated paclitaxel nanosuspensions: Interaction mechanism, direct cytosolic delivery, and signifificant improvement in pharmacokinetics. Mol. Pharm., 2015, 12(5), 1485-1500.
[http://dx.doi.org/10.1021/mp5008037]
[2]
Marrero, J.A.; Kulik, L.M.; Sirlin, C.; Zhu, A.X.; Finn, R.S.; Abecassis, M.M.; Roberts, L.R.; Heimbach, J.K. Diagnosis, staging and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases. Hepatology, 2018, 68(2), 723-750.
[http://dx.doi.org/10.1002/hep.29913]
[3]
Lin, S-R.; Chang, C-H.; Hsu, C-F.; Tsai, M-J.; Cheng, H.; Max, K.L.; Sung, P-J.; Chen, J-C.; Weng, C-F. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br. J. Pharmacol., 2020, 177(6), 1409-1423.
[http://dx.doi.org/10.1111/bph.14816]
[4]
Mo’ath, A.A.; Al-Akhras, M-A.H.; Jaafar, M.S.; Bououdina, M. Enhanced anti-cancer and antimicrobial activities of curcumin nanoparticles. Artif. Cells Nanomed. Biotechnol., 2016, 45(1), 98-107.
[5]
Tay, K-C.; Tan, L.T-H.; Chan, C.K.; Hong, S.L.; Chan, K-G.; Yap, W.H.; Pusparajah, P.; Lee, L-H.; Goh, B-H. Formononetin: A review of its anticancer potentials and mechanisms. Front. Pharmacol., 2019, 10, 820.
[http://dx.doi.org/10.3389/fphar.2019.00820]
[6]
Wang, Y.; Ma, Y.; Zheng, Y.; Song, J.; Yang, X.; Bi, C.; Zhang, D.; Zhang, Q. In vitro and in vivo anticancer activity of a novel puerarin nanosuspension against colon cancer, with high effificacy and low toxicity. Int. J. Pharm., 2013, 442(1-2), 728-735.
[http://dx.doi.org/10.1016/j.ijpharm.2012.10.021]
[7]
Qiao, H.; Chen, L.; Rui, T.; Wang, J.; Chen, T.; Fu, T.; Li, J.; Di, L. Fabrication andin vitro./in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by d-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate. Int. J. Nanomedicine, 2017, 12, 1033-1046.
[http://dx.doi.org/10.2147/IJN.S120887]
[8]
Baill, C. Cepharanthine: An update of its mode of action, pharmacological properties and medical applications. Phytomedicine, 2019, 62152956
[http://dx.doi.org/10.1016/j.phymed.2019.152956]
[9]
Unson, S.; Kongsaden, C.; Wonganan, P. Cepharanthine combined with 5-fluorouracil inhibits the growth of p53-mutant human colorectal cancer cells. J. Asian Nat. Prod. Res., 2020, 22(4), 370-385.
[http://dx.doi.org/10.1080/10286020.2018.1564136]
[10]
Payon, V.; Kongsaden, C.; Ketchart, W.; Mutirangura, A.; Wonganan, P. Mechanism of cepharanthine cytotoxicity in human ovarian cancer cells. Planta Med., 2019, 85(01), 41-47.
[http://dx.doi.org/10.1055/a-0706-7503]
[11]
Tang, Z-H.; Cao, W-X.; Guo, X.; Dai, X-Y.; Lu, J-H.; Chen, X.; Zhu, H.; Lu, J-J. Identifification of a novel autophagic inhibitor cepharanthine to enhance the anti-cancer property of dacomitinib in non-small cell lung cancer. Cancer Lett., 2018, 412, 1-9.
[http://dx.doi.org/10.1016/j.canlet.2017.10.001]
[12]
Biswas, K.K.; Tancharoen, S.; Sarker, K.P.; Kawahara, K.; Hashiguchi, T.; Maruyama, I. Cepharanthine triggers apoptosis in a human hepatocellular carcinoma cell line (HuH 7) through the activation of JNK1/2 and the downregulation of Akt. FEBS Lett., 2006, 580, 703-710.
[http://dx.doi.org/10.1016/j.febslet.2005.12.048]
[13]
Rogosnitzky, M.; Danks, R. Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions. Pharmacol. Rep., 2011, 63, 337-347.
[http://dx.doi.org/10.1016/S1734-1140(11)70500-X]
[14]
Gao, S.; Li, X.; Ding, X.; Qi, W.; Yang, Q. Cepharanthine induces autophagy, apoptosis and cell cycle arrest in breast cancer cells. Cell. Physiol. Biochem., 2017, 41, 1633-1648.
[http://dx.doi.org/10.1159/000471234]
[15]
Yallapu, M.M.; Jaggi, M.; Chauhan, S.C. β-Cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostate cancer cells. Colloids Surf. B Biointerfaces, 2010, 79, 113-125.
[http://dx.doi.org/10.1016/j.colsurfb.2010.03.039]
[16]
Noyes, A.S.; Whitney, W.R. The rate of solution of solid substances in their own solutions. J. Am. Chem. Soc., 1897, 19, 930-934.
[http://dx.doi.org/10.1021/ja02086a003]
[17]
Cerdeira, A.M.; Mazzotti, M.; Gander, B. Miconazole nanosuspensions: influence of formulation variables on particle size reduction and physical stability. Int. J. Pharm., 2010, 396, 210-218.
[http://dx.doi.org/10.1016/j.ijpharm.2010.06.020]
[18]
Wu, L.; Zhang, J.; Watanabe, W. Physical and chemical stability of drug nanoparticles. Adv. Drug Deliv. Rev., 2011, 63, 456-469.
[http://dx.doi.org/10.1016/j.addr.2011.02.001]
[19]
Qu, C.; Zhang, L.; Du, X.; Zhang, X.; Zheng, J.; Zhao, Y.; Tu, P. Preparation and evaluation of wet-milled usnic acid nanocrystalsuspension for better bioaffinity. Drug Dev. Ind. Pharm., 2018, 44(5), 707-712.
[http://dx.doi.org/10.1080/03639045.2017.1409756]
[20]
Liu, Q.; Yang, X.; Sun, J.; Yu, F.; Zhang, H.; Gao, J.; Zheng, A. Size-dependent biological effects of quercetin nanocrystals. Molecules, 2019, 24(7), 1438.
[http://dx.doi.org/10.3390/molecules24071438]
[21]
Balasubramaniam, J.; Bindu, K.; Rao, V.U.; Ray, D.; Haldar, R.; Brzeczko, A.W. Effect of sperdisintegrants on dissolution of cationic drugs. Dissolut. Technol., 2008, 15(2), 18-25.
[http://dx.doi.org/10.14227/DT150208P18]
[22]
Azad, M.; Afolabi, A.; Bhakay, A.; Leonardi, J.; Davé, R.; Bilgili, E. Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer. Eur. J. Pharm. Biopharm., 2015, 94, 372-385.
[http://dx.doi.org/10.1016/j.ejpb.2015.05.028]
[23]
Bhakay, A.; Azad, M.; Vizzotti, E.; Dave, R.N.; Bilgili, E. Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants. Drug Dev. Ind. Pharm., 2014, 40(11), 1509-1522.
[http://dx.doi.org/10.3109/03639045.2013.831442]
[24]
Park, S.H.; Shin, H.S.; Park, S.N. A novel pH-responsive hydrogel based on carboxymethyl cellulose/2-hydroxyethyl acrylate for transdermal delivery of naringenin. Carbohydr. Polym., 2018, 200, 341-352.
[http://dx.doi.org/10.1016/j.carbpol.2018.08.011]
[25]
Hasegawa, Y.; Higashi, K.; Yamamoto, K.; Moribe, K. Direct evaluation of molecular states of piroxicam/poloxamer nanosuspension by suspended-state NMR and raman spectroscopies. Mol. Pharm., 2015, 12(5), 1564-1572.
[http://dx.doi.org/10.1021/mp500872g]
[26]
Doub, W.H.; Adams, W.P.; Spencer, J.A.; Buhse, L.F.; Nelson, M.P.; Treado, P.J. Raman chemical imaging for ingredient-specific particle size characterization of aqueous suspension nasal spray formulations: A progress report. Pharm. Res., 2007, 24(5), 934-945.
[http://dx.doi.org/10.1007/s11095-006-9211-2]
[27]
Li, J.; Yang, B.; Levons, J.; Pinnamaneni, S.; Raghavan, K. Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach. J. Pharm. Sci., 2011, 100(11), 4907-4921.
[http://dx.doi.org/10.1002/jps.22659]
[28]
Anbharasi, V.; Cao, N.; Feng, S. Doxorubicin conjugated to d-a-tocopheryl polyethylene glycol succinate and folic acid as a prodrug for targeted chemotherapy. J. Biomed. Mater. Res., 2010, 94(3), 730-743.
[29]
Gao, L.; Liu, G.; Ma, J.; Wang, X.; Wang, F.; Wang, H.; Sun, J. Paclitaxel nanosuspension coated with P-gp inhibitory surfactants: II. Ability to reverse the drug-resistance of H460 human lung cancer cells. Colloids Surf. B Biointerfaces, 2014, 117, 122-127.
[http://dx.doi.org/10.1016/j.colsurfb.2014.02.016]
[30]
Lou, H.; Zhang, X.; Gao, L.; Feng, F. In vitro and in vivo antitumor activity of oridonin nanosuspension. Int. J. Pharm., 2009, 379(1), 181-186.
[http://dx.doi.org/10.1016/j.ijpharm.2009.06.022]
[31]
Lou, H.; Gao, L.; Wei, X.; Zhang, Z.; Zheng, D.; Zhang, D.; Zhang, X.; Li, Y.; Zhang, Q. Oridonin nanosuspension enhances anti-tumor effificacy in SMMC-7721 cells and H22 tumor bearing mice. Colloids Surf. B Biointerfaces, 2011, 87(2), 319-325.
[http://dx.doi.org/10.1016/j.colsurfb.2011.05.037]
[32]
Wang, J.; Sun, J.; Chen, Q.; Gao, Y.; Li, L.; Li, H.; Leng, D.; Wang, Y.; Sun, Y.; Jing, Y.; Wang, S.; He, Z. Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance. Biomaterials, 2012, 33(28), 6877-6888.
[http://dx.doi.org/10.1016/j.biomaterials.2012.06.019]
[33]
Dintaman, J.M.; Silverman, J.A. Inhibition of P-glycoprotein by D-alpha-Tocopheryl Polyethylene Glycol 1000Succinate (TPGS). Pharm. Res., 1999, 16, 1550-1556.
[http://dx.doi.org/10.1023/A:1015000503629]
[34]
Mahmoud, K.A.; Mena, J.A.; Male, K.B.; Hrapovic, S.; Kamen, A.; Luong, J.H.T. Effect of surface charge on the cellular uptake and cytotoxicity of fluorescent labeled cellulose nanocrystals. ACS Appl. Mater. Interfaces, 2010, 2, 2924-2932.
[http://dx.doi.org/10.1021/am1006222]
[35]
Ghosh, I.; Bose, S.; Vippagunta, R.; Harmon, F. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. Int. J. Pharm., 2011, 409(1-2), 260-268.
[http://dx.doi.org/10.1016/j.ijpharm.2011.02.051]
[36]
Palao-Suay, R.; Aguilar, M.R.; Parra-Ruiz, F.J.; Maji, S.; Hoogenboom, R.; Rohner, N.A.; Thomas, S.N.; San Román, J. Enhanced bioactivity of α-tocopheryl succinate based block copolymer nanoparticles by reduced hydrophobicity. Macromol. Biosci., 2016, 16(12), 1824-1837.
[http://dx.doi.org/10.1002/mabi.201600259]
[37]
Frank, L.A.; Gazzi, R.P.; de Andrade Mello, P.; Buffon, A.; Pohlmann, A.R.; Guterres, S.S. Imiquimod-loaded nanocapsules improve cytotoxicity in cervical cancer cell line. Eur. J. Pharm. Biopharm., 2019, 136, 9-17.
[http://dx.doi.org/10.1016/j.ejpb.2019.01.001]
[38]
Choudhury, H.; Gorain, B.; Pandey, M.; Kumbhar, S.A.; Tekade, R.K.; Iyer, A.K.; Kesharwani, P. Recent advances in TPGS-based nanoparticles of docetaxel for improved chemotherapy. Int. J. Pharm., 2017, 529(1-2), 506-522.
[http://dx.doi.org/10.1016/j.ijpharm.2017.07.018]
[39]
Rattanawong, A.; Payon, V.; Limpanasittikul, W.; Boonkrai, C.; Mutirangura, A.; Wonganan, P. Cepharanthine exhibits a potent anticancer activity in p53-mutated colorectal cancer cells through upregulation of p21Waf1/Cip1. Oncol. Rep., 2018, 39, 227-238.
[40]
Nagano, M.; Kanno, T.; Fujita, H.; Muranaka, S.; Fujiwara, T.; Utsumi, K. Cepharanthine, an anti-inflammatory drug, suppresses mitochondrial membrane permeability transition. Physiol. Chem. Phys. Med. NMR, 2003, 35, 131-143.
[41]
Uto, T.; Toyama, M.; Yoshinaga, K.; Baba, M. Cepharanthine induces apoptosis through the mitochondria/caspase pathway in murine dendritic cells. Immunopharmacol. Immunotoxicol., 2016, 38(3), 238-243.
[http://dx.doi.org/10.3109/08923973.2016.1173059]
[42]
Zhu, Q.; Guo, B.; Chen, L.; Ji, Q.; Liang, H.; Wen, N.; Zhang, L. Cepharanthine exerts antitumor activity on choroidal melanoma by reactive oxygen species production and c-Jun N-terminal kinase activation. Oncol. Lett., 2017, 13(5), 3760-3766.
[http://dx.doi.org/10.3892/ol.2017.5945]
[43]
Wu, J.; Suzuki, H.; Akhand, A.A.; Zhou, Y-W.; Hossain, K.; Nakashima, I. Modes of activation of mitogen-activated protein kinases and their roles in cepharanthine-induced apoptosis in human leukemia cells. Cell. Signal., 2020, 14(6), 509-515.
[http://dx.doi.org/10.1016/S0898-6568(01)00278-9]
[44]
Kumar, R.; Singh, M.; Meena, J.; Singhvi, P.; Thiyagarajan, D.; Saneja, A.; Panda, A.K. Hyaluronic acid - dihydroartemisinin conjugate: Synthesis, characterization andin vitro. evaluation in lung cancer cells. Int. J. Biol. Macromol., 2019, 133, 495-502.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.04.124]
[45]
Wang, R.; Yang, M.; Li, G.; Xin, W.; Zhang, Z.; Qiao, H.; Jun, C.; Zhipeng, C.; Xiaobin, C.; Junsong, L. Paclitaxel-betulinic acid hybrid nanosuspensions for enhanced anti-breast cancer activity. Colloids Surf. B Biointerfaces, 2019, 174, 270-279.
[http://dx.doi.org/10.1016/j.colsurfb.2018.11.029]
[46]
Constantinou, C.; Neophytou, C.M.; Vraka, P.; Hyatt, J.A.; Papas, K.A.; Constantinou, A.I. Induction of DNA damage and caspase-independent programmed cell death by vitamin E. Nutr. Cancer, 2012, 64(1), 136-152.
[http://dx.doi.org/10.1080/01635581.2012.630167]

Rights & Permissions Print Cite
Article Metrics
20
© 2024 Bentham Science Publishers | Privacy Policy