Genotoxicity of Noscapine Nanosuspension Prepared by Microfluidic Reactors on HepG2 Cell Line

Document Type : Research Article


1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, I.R. IRAN

2 Department De Bioquimica I De Biologia Molecular, Institut De Biotecnologia Biomedicina (BB), Universitat Autonoma De Barcelona, Barcelona, SPAIN

3 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, I.R. IRAN

4 Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, I.R. IRAN

5 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, I.R. IRAN

6 Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University Tehran, I.R. IRAN


Noscapine is an antispasmodic alkaloid used as antitussive and anti-cough obtained from plants in the Papaveraceae family which this benzylisoquinoline alkaloid and its synthetic subsidiaries (called noscapinoids) are being assessed for their anticancer potential.  The present research aimed to investigate the induction of DNA destruction and viability of HepG2 tumor spheroid culture influenced by noscapine and nanosuspension of noscapine. Culture of HepG2 cells as spheroids was treated with different concentrations of noscapine for 24 h on Day 11. Afterward, viability assay and alkaline comet assay methods were applied to examine the viability and induced DNA destruction, respectively. Based on the results, no significant impact was observed from Tween 40 on the viability and DNA damage levels in comparison with the control (p > 0.05). Moreover, increasing noscapine concentration resulted in a dose-dependent reduction in viability of hepatic cancer cells and elevation of DNA damages, showing a correlation between rises of DNA damages and viability decline.


Main Subjects

[1] Yadav N., Ganie SH.A., Singh B., Chhillar A.K., Yadav S.S., Phytochemical Constituents and Ethnopharmacological Properties of Ageratum Conyzoides L. Phytotherapy Research. 1:16-  (2019).
[2] Rowinsky E.K., Cazenave L.A., Donehower R.C., Taxol: a Novel Investigational Antimicrotubule Agent, J. Nat. Can. Inst., 15: 1247-1259 (1990).
[3] Bhatnagar A.S., The Discovery and Mechanism of Action of Letrozole, Breast Cancer Res Treat., 105: 7-   (2007).
[4] Stark, G.R., Progress in Understanding Multidrug Resistance, Nature, 324: 407-     (1986).
[5] J. Francis Md, N. Coakley Mlis, L. Elit Md, H. Mackay Md, And The Gynecologic Cancer Disease Site Group., Systemic Therapy for Recurrent Epithelial Ovarian Cancer: A Clinical Practice Guideline, Current Oncology, 24(6): e540–e546 (2017).
[6] Prip, Anne, Møller, Kirsten Alling, Nielsen, Dorte Lisbet, Jarden, Mary, Olsen, Marie-Helene, Danielsen, Anne Kjaergaard, The Patient–Healthcare Professional Relationship and Communicationin the Oncology Outpatient Setting, Cancer Nurs., 41(5): E11–E22 (2018).
in Cancer Chemotherapeutics, Pharmacol. Ther., 52: 35-84 (1991).
[8] Ye K., Ke Y., Keshava N., Shanks J., Kapp J.A., Tekmal R.R., Petros J., Joshi H.C., Opium Alkaloid Noscapine is an Antitumor Agent that Arrests Metaphase and Induces Apoptosis in Dividing Cells, Proc. Nat. Acad. Sci. USA, 95: 1601-1606 (1998).
[9] Altinoz M.A.,·Topcu G.,  Hacimuftuoglu, A., Ozpinar A., Ozpinar1 Hacker A.E., Elmaci I., Noscapine,
A Non‑Addictive Opioid and Microtubule‑Inhibitor in Potential Treatment of Glioblastoma
, Neurochemical Research., 145: 195-203 (2019).
[10] Karlsson M.O., Dahlstrom B., Serum Protein Binding of Noscapine: Influence ofa Reversible Hydrolysis, J. Pharm. Pharmacol., 42: 140 (1990).
[11] Quisbert-Valenzuela E.O., Gloria M. Ca., Apoptotic Effect of Noscapine in Breast Cancer Cell Lines, International Journal of Oncology, 48: 2666-2674 (2016).
[12] Christe Sonia Mary, M., Sasikumar, S., Sodium Alginate/Starch Blends Loaded with Ciprofloxacin Hydrochloride as a Floating Drug Delivery System - in Vitro Evaluation, Iran. J. Chem. Chem. Eng. (IJCCE), 34: 25-31 (2015).
[13] Schofield, J.R., Lawrence, B.A., Recognition and Management of Medication Excipient Reactivity in Patients with Mast Cell Activation Syndrome, The American Journal of the Medical Sciences. 357: 507-511 (2019).
[14] Empey D.W., Laitinen L.A., Young G.A., Bye C.E., Hughes D.T.D., Comparison of the Antitussive Effects of Codeine Phosphate 20 mg Dextromethorphan 30 mg and Noscapine 30 Mg Using Citric Acid Induced Cough in Normal Subjects, Eur. J. Clin. Pharmacol., 16: 393-397 (1979).
[15] Taghavi S.M., Momenpour M., Azarian M., Ahmadian M., Souri F., Taghavi S.A., Sadeghain M., Karchani M., Effects of Nanoparticles on the Environment and Outdoor Workplaces, Journal of Electronic Physician, 5:706-712 (2013).
[16] Yong, Ke. Á., Keqiang, Ye, Á., Hans, E. Grossniklaus, David, R., Archer, Harish Á., Joshi C., Judith Á., Kapp A., Noscapine Inhibits Tumor Growth With Little Toxicity to Normal Tissues or Inhibition of Immune Responses, Cancer Immunol. Immunother, 49: 217-225 (2000)
[17] Müller, R.H., Jacobs, C., Kayser, O., Nanosuspensions as Particulate Drug Formulations In Therapy: Rationale for Development and What We Can Expect for the Future, Adv. Drug Deliv. Rev., 47(1): 3–19 (2001).
[18] Nayak, S., Panda, D., Sahoo, J., Nanosuspension: a  Novel Drug Delivery System, J. Pharm. Res., 3(2): 241-246 (2010).
[20] Ali, S.M., York, P., Amani, A., Blagden, N., Evaluation of a Nanodispersion Formulation Prepared Through Microfluidic Reactors for Pulmonary Delivery of Budesonide Using Nebulizers, Iran J. Pharmaceut. Res., 13(3): 785-795 (2014).
[22] Patravale, V.B., Date, A.A., Kulkarni, R.M., Nanosuspensions: A Promising Drug Delivery Strategy, J. Pharm. Pharmacol., 56(7): 827–840 (2004).
[23] Kocbek, P., Baumgartner, S., Kristl, J., Preparation and Evaluation of Nanosuspensions for Enhancing the Dissolution of Poorly Soluble Drugs, Int. J. Pharm., 312(1–2): 179–186 (2006).
[24] Mokarram, A.R., Preparation and In-Vitro Evaluation of Indomethacin Nanoparticles, DARU, 18(3): 185–192 (2010).
[25] Weigl, B.H., Bardell, R.L., Cabrera, C.R., Lab-On-A-Chip for Drug Development, Adv. Drug Deliv. Rev., 55(3): 349–377 (2003).
[26] Beebe, D.J., Mensing, G.A., Walker, G.M., Physics and Applications of Microfluidics in Biology, Ann. Rev. Biomed. Eng., 4(1): 261–86 (2002).
[27] Voldman, J., Gray, M.L., Schmidt, M.A., Microfabrication in Biology and Medicine, Ann. Rev. Biomed. Eng., 1(1): 401–425 (1999).
[28] Dollet B., Van Hoeve W., Raven J.P., Marmottant P., Versluis M., Role of the Channel Geometry
on the Bubble Pinch-Off In Flowfocusing Devices,
Phys. Rev. Lett., 100(3): 34504 (2008).
[29] Rosenfeld C., Serra C., Brochon, C., Hadziioannou G., Influence of Micromixer Characteristics on Polydispersity Index of Block Copolymers Synthesized in Continuous Flow Microreactors, Lab Chip., 8(10): 1682–1687 (2008).
[30] Peppas N.A., Hilt J.Z., Thomas J.B., “Nanotechnology in Therapeutics: Current Technology and Applications”, Taylor & Francis, London (2007).
[31] Tomuleasa C., Soritau O., Rus-Ciuca D., Pop T., Todea D., Mosteanu O., Pintea B., Foris V., Susman S., Kacsό G., Irimie A., Isolation and Characterization of Hepatic Cancer Cells with Stem-Like Properties From Hepatocellular Carcinoma, J. Gastrointes. Liver Dis., 19: 61-67 (2010).
[32] Achilli T.M., Meyer J., Morgan J.R., Advances in the Formation, Use and Understanding of Multi-Cellular Spheroids, Expert Opin. Biol. Ther., 12(10): 1347–1360 (2012).
[33] Singh N.P., Mccoy M.T., Tice R.R., Schneider E.L., A Simple Technique for Quantitation of Low Levels Of DNA Damage in Individual Cells, Exp. Cell Res., 175(1): 184-191 (1988).
[34] Chen C.Y., Wang Y.F., Huang W.R., Huang Y.T., Nickel Induces Oxidative Stress and Genotoxicity
in Human Lymphocytes
, Toxicol. Appl. Pharmacol., 189(3): 153-159 (2003).
[36] Azarian M., Amani A., Faramarzi M.A., Divsalar A., Eidi A., Design and Optimization of Noscapine Nanosuspensions and Study of its Cytotoxic Effect, Journal of Biomolecular Structure and Dynamics, 37:147-155 (2017).
[37] Ghalehkhondabi, I., Ardjmand, E., Weckman, G. R., Young W.A., An Overview of Energy Demand Forecasting Methods Published in 2005–2015, Energy Syst. 8: 411–447 (2017).
 [38] Scholten, K., Collin, W. R., Fan, X., Zellers, E.T., Nanoparticle-Coated Micro-Optofluidic Ring Resonator as a Detector for Microscale Gas Chromatographic Vapor Analysis, Nanoscale, 7: 9282–9289 (2015).
[39] Mollahasani, A., Alavi, A.H., Gandomi, A.H., Empirical Modeling of Plate Load Test Moduli of Soil via Gene Expression Programming, Comput. Geotech., 38: 281-286 (2011).
[40] Roy, P.P., Roy, K., On Some Aspects of Variable Selection for Partial Least Squares Regression Models, QSAR Comb. Sci., 27: 302-313 (2008).
[41] Segal, M.S., Goldstein, M.M., Attinger, E.O., The Use of Noscapine (Narcotine) as an Antitussive Agent, Dis. Chest., 32: 305-309 (1957).
[42] Mostafavi, E.S., Mousavi, S.M., Hosseinpour, F., Gene Expression Programming as a Basis for New Generation of Electricity Demand Prediction Models, Comp Indus. Engin., 74: 120–128 (2014).
[43] Alavi A.H., Aminian P., Gandomi A.H., Esmaeili M.A., Genetic-Based Modeling of Uplift Capacity of Suction Caissons, Exp. Sys. Applic., 38: 12608-12618 (2011).
[44] Dahlstrom B., Mellstrand T., Lofdahl C.G., Johansson M., Pharmakokinetic Properties of Noscapine, Eur. J. Clin. Pharmacol., 22: 535-539 (1982).
[45] Mooraki A., Jenabi A., Jabbari M., Zolfaghari, M, Javanmardi, S., Mahmoudian M., Bastani, B., Noscapine Suppresses Angiotensin Converting Enzyme Inhibitors‐Induced Cough, Nephrol., 10: 348-350 (2005).
[46] Karlsson M.O., Dahlstrom B., Eckernas S.A., Johansson M., Tufvesson-Alm A., Pharmacokinetics of Oral Noscapine, Eur. J. Clin. Pharmacol., 39: 275-279 (1990).
[47] Ebrahimi S.A., Zareie Rostami P., Mahmoudian M., Interaction of Noscapine with the Bradykinin Mediation of the Cough Response, Acta Physiol. Hun., 90: 147-155 (2003).
[48] Mahmoudian, M., Recent Progress in Clinical Application of Noscapine: A Review, Cur. Top. Pharmacol., 10: 81-86 (2006).
[49] Khodarahmi P., Rostami P., Rashidi A., Khodarahmi Qahnavieh I., Anxiolytic Effect of Noscapine in Mice., Pharmacological Reports, 58: 568-570 (2006). 
[51] Chougule M.B., Patel A.R., Jackson T., Singh M., Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer, Plos ONE, 6(3): E17733 (2011).
[52] Cukierman E., Khan D.R., The Benefits and Challenges Associated with the Use of Drug Delivery Systems in Cancer Therapy, Biochem. Pharmacol., 80(5): 762-770 (2010).