Evaluation of Antitumor Activity and Hepatoprotective Effect of Mitomycin C Solubilized in Chamomile Oil Nanoemulsion

Author(s): Waad A. Al-Otaibi, Mayson H. Alkhatib*, Abdulwahab N. Wali.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 10 , 2019

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Graphical Abstract:


Purpose: The present study aimed to investigate the antitumor activity and hepatoprotective effect of the MTC, when combined with CHAM oil nanoemulsion (NE), (CHAM-MTC) on the tumor growth.

Materials/Methods: The in vitro study assessed the antineoplastic effect of CHAM-MTC on the MCF-7 breast cancer cells while the in vivo therapeutic effectiveness and toxicities of CHAM-MTC were evaluated in Ehrlich Ascites Carcinoma (EAC) bearing mice. One hundred female Swiss albino mice, divided equally into non-EAC group (negative control), untreated EAC group (positive control) and three EAC groups received once intraperitoneal injection of 0.2ml CHAM-NE, 0.2ml Normal Saline (NS) contained MTC (1mg/kg) and 0.2ml CHAM-NE mixed with MTC (1mg/kg), respectively.

Results: The in vitro results indicated that CHAM-NE could potentiate the effect of MTC in sub-effective concentrations since the half-maximal inhibitory concentration (IC50) was reduced by a factor of 21.94 when compared to the MTC-NS. The in vivo study revealed that mice treated with CHAM-MTC showed a significant increase in the median survival time (MST= 37 days) when compared to the MTC-NS treated group (MST= 29.50 days). In addition, CHAM-MTC showed protective ability against the oxidative stress and hepatic damage induced by EAC and MTC treatment.

Conclusion: The combination of MTC with CHAM-NE could be valuable in enhancing the therapeutic efficacy of MTC against EAC and in eliminating MTC-induced hepatotoxicity.

Keywords: Hepatotoxicity, oxidative stress, antioxidants, nanoemulsion, essential oils, mitomycin C.

Gad, S.E. Mitomycin C.In Encyclopedia of Toxicology (Third Edition),; Wexler, P., Ed.; Academic Press: Oxford, 2014, pp. 354-356.
Crooke, S.T.; Bradner, W.T.; Mitomycin, C. A review. Cancer Treat. Rev., 1976, 3(3), 121-139.
Rjiba-Touati, K.; Ayed-Boussema, I.; Belarbia, A.; Mokni, M.; Achour, A.; Bacha, H.; Abid, S. Role of recombinant human erythropoietin against mitomycin C-induced cardiac, hepatic and renal dysfunction in Wistar rats. Hum. Exp. Toxicol., 2015, 34(5), 468-478.
Pirnia, F.; Schneider, E.; Betticher, D.; Borner, M. Mitomycin C induces apoptosis and caspase-8 and-9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ., 2002, 9(9), 905.
Boamah, E.K.; White, D.E.; Talbott, K.E.; Arva, N.C.; Berman, D.; Tomasz, M.; Bargonetti, J. Mitomycin-DNA adducts induce p53-dependent and p53-independent cell death pathways. ACS Chem. Biol., 2007, 2(6), 399-407.
Tomasz, M.; Mitomycin, C. Small, fast and deadly (but very selective). Chem. Biol., 1995, 2(9), 575-579.
Emanuel’, N.; Bogdanov, G.; Orlov, V. Free-radical mechanisms in the cytotoxic action of antitumour antibiotics. Russ. Chem. Rev., 1984, 53(12), 1121-1138.
Li, F.; Xu, J.; Zhou, J.; Zhao, L.; Sheng, J.; Sun, G.; Hu, Q. Inhibition of mitomycin C-induced chromosomal aberrations by micrometer powder of selenium-enriched green tea in mice spermatocytes. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2009, 675(1), 11-16.
Maatouk, M.; Mustapha, N.; Mokdad-Bzeouich, I.; Chaaban, H.; Ioannou, I.; Ghedira, K.; Ghoul, M.; Chekir-Ghedira, L. Heated naringin mitigate the genotoxicity effect of Mitomycin C in BALB/c mice through enhancing the antioxidant status. Biomed. Pharmacother., 2018, 97, 1417-1423.
Wang, Y.; Gray, J.P.; Mishin, V.; Heck, D.E.; Laskin, D.L.; Laskin, J.D. Distinct roles of cytochrome P450 reductase in mitomycin C redox cycling and cytotoxicity. Mol. Cancer Ther., 2010, 9(6), 1852-1863.
Marinelli, A.; de Brauw, L.M.; Beerman, H.; Keizer, H.J.; van Bockel, J.H.; Tjaden, U.R.; van de Velde, C.J. Isolated liver perfusion with mitomycin C in the treatment of colorectal cancer metastases confined to the liver. Jpn. J. Clin. Oncol., 1996, 26(5), 341-350.
Verweij, J.; Stoter, G. Severe side effects of the cytotoxic drug mitomycin-C. Neth. J. Med., 1987, 30, 43-50.
Castañeda, F.; Kinne, R.K. Effects of doxorubicin, mitomycin C, and ethanol on Hep-G2 cells in vitro. J. Cancer Res. Clin. Oncol., 1999, 125(1), 1-8.
Sturgill, M.G.; Lambert, G.H. Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function. Clin. Chem., 1997, 43(8), 1512-1526.
Lazarus, H.M.; Gottfried, M.R.; Herzig, R.H.; Phillips, G.L.; Weiner, R.S.; Sarna, G.P.; Fay, J.; Wolff, S.N.; Sudilovsky, O.; Gale, R.P. Veno‐occlusive disease of the liver after high‐dose mitomycin C therapy and autologous bone marrow transplantation. Cancer, 1982, 49(9), 1789-1795.
Gautam, N.; Mantha, A.K.; Mittal, S. Essential oils and their constituents as anticancer agents: A mechanistic view. BioMed Res. Int., 2014, 2014, 23.
Asbahani, A.E.; Miladi, K.; Badri, W.; Sala, M.; Addi, E.H.A.; Casabianca, H.; Mousadik, A.E.; Hartmann, D.; Jilale, A.; Renaud, F.N.R.; Elaissari, A. Essential oils: From extraction to encapsulation. Int. J. Pharm., 2015, 483(1), 220-243.
Monge-Fuentes, V.; Muehlmann, L.A.; Longo, J.P.F.; Silva, J.R.; Fascineli, M.L.; de Souza, P.; Faria, F.; Degterev, I.A.; Rodriguez, A.; Carneiro, F.P. Photodynamic therapy mediated by acai oil (Euterpe oleracea Martius) in nanoemulsion: A potential treatment for melanoma. J. Photochem. Photobiol. B, 2017, 166, 301-310.
Mostafa, D.M.; Kassem, A.A.; Asfour, M.H.; Al Okbi, S.Y.; Mohamed, D.A.; Hamed, T.E-S. Transdermal cumin essential oil nanoemulsions with potent antioxidant and hepatoprotective activities: In vitro and in vivo evaluation. J. Mol. Liq., 2015, 212, 6-15.
Periasamy, V.S.; Athinarayanan, J.; Alshatwi, A.A. Anticancer activity of an ultrasonic nanoemulsion formulation of Nigella sativa L. essential oil on human breast cancer cells. Ultrason. Sonochem., 2016, 31, 449-455.
Choi, M-J.; Soottitantawat, A.; Nuchuchua, O.; Min, S-G.; Ruktanonchai, U. Physical and light oxidative properties of eugenol encapsulated by molecular inclusion and emulsion-diffusion method. Food Res. Int., 2009, 42(1), 148-156.
Wei, A.; Shibamoto, T. Antioxidant/lipoxygenase inhibitory activities and chemical compositions of selected essential oils. J. Agric. Food Chem., 2010, 58(12), 7218-7225.
Roby, M.H.H.; Sarhan, M.A.; Selim, K.A-H.; Khalel, K.I. Antioxidant and antimicrobial activities of essential oil and extracts of fennel (Foeniculum vulgare L.) and chamomile (Matricaria chamomilla L.). Ind. Crops Prod., 2013, 44, 437-445.
Rekka, E.A.; Kourounakis, A.P.; Kourounakis, P.N. Investigation of the effect of chamazulene on lipid peroxidation and free radical processes. Res. Commun. Mol. Pathol. Pharmacol., 1996, 92(3), 361-364.
Wei, A.; Shibamoto, T. Antioxidant activities and volatile constituents of various essential oils. J. Agric. Food Chem., 2007, 55(5), 1737-1742.
Bhaskaran, N.; Shukla, S.; Srivastava, J.K.; Gupta, S. Chamomile: An anti-inflammatory agent inhibits inducible nitric oxide synthase expression by blocking RelA/p65 activity. Int. J. Mol. Med., 2010, 26(6), 935-940.
Srivastava, J.K.; Pandey, M.; Gupta, S. Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity. Life Sci., 2009, 85(19-20), 663-669.
Fabian, D.; Juhás, Š.; Bukovská, A.; Bujňáková, D.; Grešáková, Ľ.; Koppel, J. Anti-inflammatory effects of chamomile essential oil in mice. Slovak J. Anim. Sci., 2011, 44, 111-116.
Srivastava, J.K.; Gupta, S. Antiproliferative and apoptotic effects of chamomile extract in various human cancer cells. J. Agric. Food Chem., 2007, 55(23), 9470-9478.
Salem, M.L.; Khamis, A.A-H.; Mostafa, A-H.A-H.; Ali, E.M. Antitumor potential of some selective medicinal plants on experimental tumor ascites. J. Investig. Biochem., 2017, 6, 28-36.
Alkhatib, M.H.; Al-Otaibi, W.A.; Wali, A.N. Antineoplastic activity of mitomycin C formulated in nanoemulsions-based essential oils on HeLa cervical cancer cells. Chem. Biol. Interact., 2018, 291, 72-80.
Bilia, A.R.; Piazzini, V.; Guccione, C.; Risaliti, L.; Asprea, M.; Capecchi, G.; Bergonzi, M.C. Improving on nature: the role of nanomedicine in the development of clinical natural drugs. Planta Med., 2017, 83(05), 366-381.
Council, N.R. Guide for the Care and Use of Laboratory Animals; National Academies Press, 2010.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1), 55-63.
Khatune, N.A.; Islam, M.E.; Rahman, M.A.A.; Mosaddik, M.A.; Haque, M.E. In vivo cytotoxic evaluation of new benzofuran derivative isolated from Nyctanthes arbor-tristis L. on Ehrlich Ascite Carcinoma cells (EAC) in mice. J. Med. Sci., 2003, 3(2), 169-173.
Devbhuti, D.; Gupta, J.; Devbhuti, P. Studies on antitumor activity of Bryophyllum calycinum Salisb. against Ehrlich ascites carcinoma in Swiss albino mice. J. Pharm. Sci. Technol., 2012, 2(1), 31-33.
Regan, R.D.; Fenyk-Melody, J.E.; Tran, S.M.; Chen, G.; Stocking, K.L. Comparison of submental blood collection with the retroorbital and submandibular methods in mice (Mus musculus). J. Am. Assoc. Lab. Anim. Sci., 2016, 55(5), 570-576.
Gupta, M.; Mazumder, U.K.; Kumar, R.S.; Kumar, T.S. Antitumor activity and antioxidant role of Bauhinia racemosa against Ehrlich ascites carcinoma in Swiss albino mice. Acta Pharmacol. Sin., 2004, 25, 1070-1076.
Anon, I. Optimized standard method for quantitative determination of alkaline phosphatase. Biochemistry, 1970, 8, 658.
Kei, S. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin. Chim. Acta, 1978, 90(1), 37-43.
Aebi, H. Catalase in vitro.Methods Enzymology; Elsevier, 1984, Vol. 105, pp. 121-126.
Nishikimi, M.; Rao, N.A.; Yagi, K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem. Biophys. Res. Commun., 1972, 46(2), 849-854.
Goldberg, D.; Spooner, R. Methods of enzymatic analysis. Bergmeyer HV, 1983, 3, 258-265.
Levring, T.B.; Kongsbak, M.; Rode, A.K.O.; Woetmann, A.; Ødum, N.; Bonefeld, C.M.; Geisler, C. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis. Oncotarget, 2015, 6(26), 21853-21864.
Boufadi, Y.M.; Van Antwerpen, P.; Chikh Alard, I.; Nève, J.; Djennas, N.; Riazi, A.; Soubhye, J. Antioxidant effects and bioavailability evaluation of propolis extract and its content of pure polyphenols. J. Food Biochem., 2018, 42(1)e12434
Fischer, A.H.; Jacobson, K.A.; Rose, J.; Zeller, R. Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc., 2008, 2008(5)pdb. prot4986
Al-Otaibi, W.A.; Alkhatib, M.H.; Wali, A.N. Cytotoxicity and apoptosis enhancement in breast and cervical cancer cells upon coadministration of mitomycin C and essential oils in nanoemulsion formulations. Biomed. Pharmacother., 2018, 106, 946-955.
Gabizon, A.A.; Tzemach, D.; Horowitz, A.T.; Shmeeda, H.; Yeh, J.; Zalipsky, S. Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes. Clin. Cancer Res., 2006, 12(6), 1913-1920.
Zhou, Q.M.; Zhang, H.; Lu, Y.Y.; Wang, X.F.; Su, S.B. Curcumin reduced the side effects of mitomycin C by inhibiting GRP58‐mediated DNA cross‐linking in MCF‐7 breast cancer xenografts. Cancer Sci., 2009, 100(11), 2040-2045.
Navarrete, A.; Armitage, E.G.; Musteanu, M.; García, A.; Mastrangelo, A.; Bujak, R.; López-Casas, P.P.; Hidalgo, M.; Barbas, C. Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer. Pharmacol. Res., 2014, 2(6), 12.
Hoek-van den Hil, E.F.; Schothorst, E.M.; Stelt, I.; Swarts, H.J.; Vliet, M.; Amolo, T.; Vervoort, J.J.; Venema, D.; Hollman, P.C.; Rietjens, I.M. Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice. Genes Nutr., 2015, 10(4), 23.
Jacob, L.; Latha, M. Anticancer activity of Clitoria ternatea linn. against Dalton’s lymphoma. J. Pharmacogn. Phytochem., 2012, 4(4), 207-212.
Rioja, A.; Pizzey, A.R.; Marson, C.M.; Thomas, N.S.B. Preferential induction of apoptosis of leukaemic cells by farnesol. FEBS Lett., 2000, 467(2-3), 291-295.
Adany, I.; Yazlovitskaya, E.M.; Haug, J.S.; Voziyan, P.A.; Melnykovych, G. Differences in sensitivity to farnesol toxicity between neoplastically-and non-neoplastically-derived cells in culture. Cancer Lett., 1994, 79(2), 175-179.
Yazlovitskaya, E.M.; Melnykovych, G. Selective farnesol toxicity and translocation of protein kinase C in neoplastic HeLa-S3K and non-neoplastic CF-3 cells. Cancer Lett., 1995, 88(2), 179-183.
Horn, T.L.; Long, L.; Cwik, M.J.; Morrissey, R.L.; Kapetanovic, I.M.; McCormick, D.L. Modulation of hepatic and renal drug metabolizing enzyme activities in rats by subchronic administration of farnesol. Chem. Biol. Interact., 2005, 152(2-3), 79-99.
Duncan, R.E.; Archer, M.C. Farnesol decreases serum triglycerides in rats: identification of mechanisms including up-regulation of PPARα and down-regulation of fatty acid synthase in hepatocytes. Lipids, 2008, 43(7), 619-627.
Joo, J.H.; Jetten, A.M. Molecular mechanisms involved in farnesol-induced apoptosis. Cancer Lett., 2010, 287(2), 123-135.
Salem, F.S.; Badr, M.; Neamat-Allah, A. Biochemical and pathological studies on the effects of levamisole and chlorambucil on Ehrlich ascites carcinoma-bearing mice. Vet. Ital., 2011, 47(1)89e95
Badr, O.M.; Sakr, S.A.; Abd-Eltawab, H.M. Ameliorative effect of ginger extract against pathological alterations induced in mice bearing solid tumors. JBAAR, 2016, 2(3), 185-196.
Patra, S.; Muthuraman, M.S.; Prabhu, A.; Priyadharshini, R.R.; Parthiban, S. Evaluation of antitumor and antioxidant activity of Sargassum tenerrimum against Ehrlich ascites carcinoma in mice. Asian Pac. J. Cancer Prev., 2015, 16(3), 915-921.
Soliman, A.M.; Fahmy, S.R.; El-Abied, S.A. Anti-neoplastic activities of sepia officinalis ink and Coelatura aegyptiaca extracts against Ehrlich ascites carcinoma in Swiss albino mice. Int. J. Clin. Exp. Pathol., 2015, 8(4), 3543.
Kathiriya, A.; Das, K.; Kumar, E.; Mathai, K. Evaluation of antitumor and antioxidant activity of Oxalis corniculata linn. against ehrlich ascites carcinoma on mice. Iran. J. Cancer Prev., 2010, 3(4), 157-165.
Stanojevic, L.P.; Marjanovic-Balaban, Z.R.; Kalaba, V.D.; Stanojevic, J.S.; Cvetkovic, D.J. Chemical composition, antioxidant and antimicrobial activity of chamomile flowers essential oil (Matricaria chamomilla L.). J. Essent. Oil Bear. Pl., 2016, 19(8), 2017-2028.
Srivastava, J.K.; Shankar, E.; Gupta, S. Chamomile: A herbal medicine of the past with a bright future. Mol. Med. Rep., 2010, 3(6), 895-901.
Sharafzadeh, S.; Alizadeh, O. German and Roman chamomile. J. Appl. Pharm. Sci, 2011, 1(10), 01-05.
Greenstein, J.P. The in vivo effect on liver catalase by a tumor1. J. Natl. Cancer Inst., 1955, 15(Supplement_5)1603-1605
Yamaguchi, Y.; Sato, K.; Endo, H. Depression of catalase gene expression in the liver of tumor bearing nude mice. Biochem. Biophys. Res. Commun., 1992, 189(2), 1084-1089.
Xu, B.H.; Gupta, V.; Singh, S.V. Characterization of a human bladder cancer cell line selected for resistance to mitomycin C. Int. J. Cancer, 1994, 58(5), 686-692.
Arnér, E.S.; Holmgren, A. Physiological functions of thioredoxin and thioredoxin reductase. Eur. J. Biochem., 2000, 267(20), 6102-6109.
Paz, M.M.; Zhang, X.; Lu, J.; Holmgren, A. A new mechanism of action for the anticancer drug mitomycin C: Mechanism-based inhibition of thioredoxin reductase. Chem. Res. Toxicol., 2012, 25(7), 1502-1511.
Constantinescu, A.; Pick, U.; Handelman, G.; Haramaki, N.; Han, D.; Podda, M.J.; Tritschler, H.; Packer, L. Reduction and transport of lipoic acid by human erythrocytes. Biochem. Pharmacol., 1995, 50(2), 253-261.
Okuda, J.; Hirai, Y.; Hayazaki, T. Mechanism of inhibition of erythrocyte glutathione reductase by Mitomycin-C. Clin. Chim. Acta, 1989, 181(1), 37-46.
Tur, L.; Bayşu Sözbilir, N. Effects of Matricaria chamomilla L. on lipid peroxidation, antioxidant enzyme systems, and key liver enzymes in CCl4-treated rats. Toxicol. Environ. Chem., 2012, 94(9), 1780-1788.
Bhaskaran, N.; Srivastava, J.K.; Shukla, S.; Gupta, S. Chamomile confers protection against hydrogen peroxide-induced toxicity through activation of Nrf2-mediated defense response. Phytother. Res., 2013, 27(1), 118-125.
Lisanti, M.P.; Martinez-Outschoorn, U.E.; Lin, Z.; Pavlides, S.; Whitaker-Menezes, D.; Pestell, R.G.; Howell, A.; Sotgia, F. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs” fertilizer. Cell Cycle, 2011, 10(15), 2440-2449.

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Year: 2019
Page: [1232 - 1242]
Pages: 11
DOI: 10.2174/1871520619666190408114732
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