Abstract
Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB-07 (2000 μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD50 (50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdel-Latif MS, Elmeleigy KM, Aly TAA, Khattab MS, Mohamed SM (2017) Pathological and biochemical evaluation of coumarin and chlorophyllin against aflatoxicosis in rat. Exp Toxicol Pathol 69(5):285–291. https://doi.org/10.1016/j.etp.2017.01.014
Agrawal SS, Saraswati S, Mathur R, Pandey M (2011) Cytotoxic and antitumor effects of brucine on Ehrlich ascites tumor and human cancer cell line. Life Sci 89(5–6):147–158. https://doi.org/10.1016/j.lfs.2011.05.020
Akah PA, Osigwe CC, Nworu CS (2010) Reversal of coumarin-induced toxicity by the extracts and fractions of Ageratum conyzoides. Asian J Med Sci 2(3):121–126
Almeida RN, Falcão ACGM, Diniz RST, Quintans-Júnior LJ, Polari RM, Barbosa-Filho JM, Agra MF, Duarte JC, Ferreira CD, Antoniolli AR, Araújo CC (1999) Metodologia para avaliação de plantas com atividade no Sistema Nervoso Central e alguns dados experimentais. Rev Bras Farm 80(3/4):72–76
Amelo W, Nagpal P, Makonnen E (2014) Antiplasmodial activity of solvent fractions of methanolic root extract of Dodonaea angustifolia in Plasmodium berghei infected mice. BMC Complement Altern Med 14:462–469. https://doi.org/10.1186/1472-6882-14-462
Araújo RS, Guerra FQ, Lima EO, Simone CA, Tavares JF, Scotti L, Scotti MT, Aquino TM, Moura RO, Mendonça FJ, Barbosa-Filho JM (2013) Synthesis, structure- activity relationships (SAR) and in silico studies of coumarin derivatives with antifungal activity. Int J Mol Sci 14(1):1293–1309. https://doi.org/10.3390/ijms14011293
Baba M, Jin Y, Mizuno A, Suzuki H, Okada Y, Takasuka N, Tokuda H, Nishino H, Okuyama T (2002) Studies on cancer chemoprevention by traditional folk medicines XXIV - inhibitory effect of a coumarin derivative, 7-isopentenyloxycoumarin, against tumor-promotion. Biol Pharm Bull 25(2):244–246. https://doi.org/10.1248/bpb.25.244
Barot KP, Jain SV, Kremer L, Singh S, Ghate MD (2015) Recent advances and therapeutic journey of coumarins: current status and perspectives. Med Chem Res 24:2771–2798. https://doi.org/10.1007/s00044-015-1350-8
Bazzaz BSF, Iranshahi M, Naderinasab M, Hajian S, Sabeti Z, Masumi E (2010) Evaluation of the effects of galbanic acid from Ferula szowitsiana and conferol from F. badrakema, as modulators of multi-drug resistance in clinical isolates of Escherichia coli and Staphylococcus aureus. Res Pharm Sci 5(1):25–32
Belli C, Trapani D, Viale G, D'Amico P, Duso BA, Della Vigna P, Orsi F, Curigliano G (2018) Targeting the microenvironment in solid tumors. Cancer Treat Rev 65:22–32. https://doi.org/10.1016/j.ctrv.2018.02.004
Benci K, Mandić L, Suhina T, Sedić M, Klobučar M, Kraljević PS, Pavelić K, Wittine K, Mintas M (2012) Novel coumarin derivatives containing 1,2,4-triazole, 4,5-dicyanoimidazole and purine moieties: synthesis and evaluation of their cytostatic activity. Molecules 17(9):11010–11025. https://doi.org/10.3390/molecules170911010
Benedito R, Hellström M (2013) Notch as a hub for signaling in angiogenesis. Exp Cell Res 319(9):1281–1288. https://doi.org/10.1016/j.yexcr.2013.01.010
Cao D, Liu Y, Yan W, Wang C, Bai P, Wang T, Tang M, Wang X, Yang Z, Ma B, Ma L, Lei L, Wang F, Xu B, Zhou Y, Yang T, Chen L (2016) Design, synthesis, and evaluation of in vitro and in vivo anticancer activity of 4-substituted coumarins: a novel class of potent tubulin polymerization inhibitors. J Med Chem 59(12):5721–5739. https://doi.org/10.1021/acs.jmedchem.6b00158
Carol A (1995) Acute, sub chronic and chronic toxicology, handbook of toxicology. CRC Press, Florida
Carpinella MC, Ferrayoli CG, Palacios SM (2005) Antifungal synergistic effect of scopoletin, a hydroxycoumarin isolated from Melia azedarach L. fruits. J Agric Food Chem 53:2922–2927. https://doi.org/10.1021/jf0482461
Choi Y, Seo H, Han J, Yoo I, Kim J, Ka H (2016) Chemokine (C-C motif) ligand 28 and its receptor CCR10: expression and function at the maternal-conceptus interface in pigs. Biol Reprod 95(4):84–94. https://doi.org/10.1095/biolreprod.116.141903
Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 1830(6):3670–3695. https://doi.org/10.1016/j.bbagen.2013.02.008
Denny KH, Stewart CW (2017) Acute, sub-acute, sub-chronic and chronic general toxicity testing for preclinical drug development. In: Faqi AS (ed) A comprehensive guide to toxicology in preclinical drug development, 2nd edn. Elsevier, Amsterdam, pp 87–105
Fardini Y, Dehennaut V, Lefebvre T, Issad T (2013) O-GlcNAcylation: a new cancer hallmark? Front Endocrinol 4:1–14. https://doi.org/10.3389/fendo.2013.00099
Fedato RP, Maistro EL (2014) Absence of genotoxic effects of the coumarin derivative 4-methylesculetin in vivo and its potential chemoprevention against doxorubicin-induced DNA damage. J Appl Toxicol 34(1):33–39. https://doi.org/10.1002/jat.2823
GAD SC (2007) Animal models in toxicology. CRC Press, Florida
Gu D, Chen Z, Zhao H, Du W, Xue F, Ge J, Sui T, Wu H, Liu B, Lu S, Zhang L, Yang R (2010) Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia. Hum Immunol 71(6):586–591. https://doi.org/10.1016/j.humimm.2010.02.010
Guerra FQ, Araújo RS, Sousa JP, Pereira FO, Mendonça-Junior FJ, Barbosa-Filho JM, Oliveira LE (2015) Evaluation of antifungal activity and mode of action of new coumarin derivative, 7-hydroxy-6-nitro-2h-1-benzopyran-2-one, against Aspergillus spp. Evid Based Complement Alternat Med 2015:1–8. https://doi.org/10.1155/2015/925096
Gurrapu S, Jonnalagadda SK, Alam MA, Ronayne CT, Nelson GL, Solano LN, Lueth EA, Drewes LR, Mereddy VR (2016) Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: in vitro and in vivo studies as potential anticancer agents. Bioorg Med Chem Lett 26(14):3282–3286. https://doi.org/10.1016/j.bmcl.2016.05.054
Haghighi F, Matin MM, Bahrami AR, Iranshahi M, Rassouli FB, Haghighitalab A (2014) The cytotoxic activities of 7-isopentenyloxycoumarin on 5637 cells via induction of apoptosis and cell cycle arrest in G2/M stage. DARU J Pharm Sci 22(1):1–10. https://doi.org/10.1186/2008-2231-22-3
Hamdi N, Al-Ayed AS, Ben Said R, Fabienne A (2012) Synthesis and characterization of new thiazolidinones containing coumarin moieties and their antibacterial and antioxidant activities. Molecules 17:9321–9334. https://doi.org/10.3390/molecules17089321
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013
Iranshahi M, Askari M, Sahebkar A, Adjipavlou-Litina D (2009) Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. DARU J Pharm Sci 17:99–103
Kang C, Munawir A, Cha M, Sohn ET, Lee H, Kim JS, Yoon WD, Lim D, Kim E (2009) Cytotoxicity and hemolytic activity of jellyfish Nemopilema nomurai (Scyphozoa: Rhizostomeae) venom. Comp Biochem Physiol C Toxicol Pharmacol 150(1):85–90. https://doi.org/10.1016/j.cbpc.2009.03.003
Kasumbwe K, Venugopala KN, Mohanlall V, Odhav B (2017) Synthetic mono/di-halogenated coumarin derivatives and their anticancer properties. Anti Cancer Agents Med Chem 17(2):276–285
Kraljević TG, Harej A, Sedić M, Pavelić SK, Stepanić V, Drenjančević D, Talapko J, Raić-Malić S (2016) Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids. Eur J Med Chem 124:794–808. https://doi.org/10.1016/j.ejmech.2016.08.062
Lin KT, Lien JC, Chung CH, Kuo SC, Huang TF (2012) Bp5250 inhibits vascular endothelial growth factor-induced angiogenesis and HIF-1α expression on endothelial cells. Naunyn Schmiedeberg's Arch Pharmacol 385(1):39–49. https://doi.org/10.1007/s00210-011-0690-2
Liu H, Wang Y, Sharma A, Mao R, Jiang N, Dun B, She JX (2015) Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling. Anti-Cancer Drugs 26(6):667–677. https://doi.org/10.1097/CAD.0000000000000232
Maistro EL, Souza Marques E, Fedato RP, Tolentino F, Silva CA, Tsuboy MS, Resende FA, Varanda EA (2015) In vitro assessment of mutagenic and genotoxic effects of coumarin derivatives 6,7-dihydroxycoumarin and 4-methylesculetin. J Toxicol Environ Health 78(2):109–118. https://doi.org/10.1080/15287394.2014.943865
Mangueira VM, Batista TM, Brito MT, Sousa TKG, Cruz RMDD, Abrantes RA, Veras RC, Medeiros IA, Medeiros KKP, Pereira ALDC, Serafim VL, Moura RO, Sobral MV (2017) A new acridine derivative induces cell cycle arrest and antiangiogenic effect on Ehrlich ascites carcinoma model. Biomed Pharmacother 90:253–261. https://doi.org/10.1016/j.biopha.2017.03.049
Marques ES, Salles DB, Maistro EL (2015) Assessment of the genotoxic/clastogenic potential of coumarin derivative 6,7-dihydroxycoumarin (aesculetin) in multiple mouse organs. Toxicol Rep 2:268–274. https://doi.org/10.1016/j.toxrep.2015.01.005
Martirosyan A, Petrek M, Kishore A, Manukyan G (2016) Immunomodulatory effects of therapeutic plasma exchange on monocytes in antiphospholipid syndrome. Exp Ther Med 12(2):1189–1195. https://doi.org/10.3892/etm.2016.3441
Meireles DRP, Fernandes HMB, Rolim TL, Batista TM, Mangueira VM, Sousa TKG, Pita JCLR, Xavier AL, Beltrão DM, Tavares JF, Silva MS, Medeiros KKP, Sobral MV (2016) Toxicity and antitumor efficacy of Croton polyandrus oil against Ehrlich ascites carcinoma cells. Rev Bras Farmacogn 26:751–758. https://doi.org/10.1016/j.bjp.2016.05.014
Mendanha SA, Moura SS, Anjos JL, Valadares MC, Alonso A (2013) Toxicity of terpenes on fibroblast cells compared to their hemolytic potential and increase in erythrocyte membrane fluidity. Toxicol in Vitro 27(1):323–329. https://doi.org/10.1016/j.tiv.2012.08.022
Oliveira LP, Pinheiro RC, Vieira MS, Paula JR, Bara MT, Valadares MC (2010) Atividade citotóxica e antiangiogênica de Punica granatum L., Punicaceae. Rev Bras Farmacogn 20(2):201–207. https://doi.org/10.1590/S0102-695X2010000200011
Olmedo D, Sancho R, Bedoya LM, López-Pérez JL, Del Olmo E, Muñoz E, Alcamí J, Gupta MP, San Feliciano A (2012) 3-Phenylcoumarins as inhibitors of HIV-1 replication. Molecules 17:9245–9257. https://doi.org/10.3390/molecules17089245
Organisation for Economic Co-operation and Development (OECD) (1997) Guideline for Testing of Chemicals n. 474: mammalian erythrocyte micronucleus test. OECD, Paris, pp 1–10
Organisation for Economic Co-operation and Development (OECD) (2001) Guideline for Testing of Chemicals n. 423: acute oral toxicity. OECD, Paris, pp 1–14
Patel H, Nilendu P, Jahagirdar D, Pal JK, Sharma NK (2018) Modulating secreted components of tumor microenvironment: a masterstroke in tumor therapeutics. Cancer Biol Ther 19(1):3–12. https://doi.org/10.1080/15384047.2017.1394538
Pereira EC, Lucetti DL, Barbosa-Filho JM, Brito EM, Monteiro VS, Patrocínio MC, Moura RR, Leal LK, Macedo DS, Sousa FC, Barros Viana GS, Vasconcelos SM (2009) Coumarin effects on amino acid levels in mice prefrontal cortex and hippocampus. Neurosci Lett 454(2):139–142. https://doi.org/10.1016/j.neulet.2009.03.009
Pozarowski P, Darzynkiewicz Z (2004) Analysis of cell cycle by flow cytometry. Methods Mol Biol 281:301–311. https://doi.org/10.1385/1-59259-811-0:301
Rageh MM, El-Gebaly RH, Afifi MM (2018) Antitumor activity of silver nanoparticles in Ehrlich carcinoma-bearing mice. Naunyn Schmiedeberg's Arch Pharmacol 391(12):1421–1430. https://doi.org/10.1007/s00210-018-1558-5
Renzi D, Valtolina M, Foster R (1993) The evaluation of a multi-endpoint cytotoxicity assay system. ATLA 21:89–96
Rolim TL, Meireles DRP, Batista TM, Sousa TKG, Mangueira VM, Abrantes RA, Pita JCLR, Xavier AL, Costa VCO, Batista LM, Silva MS, Sobral MV (2017) Toxicity and antitumor potential of Mesosphaerum sidifolium (Lamiaceae) oil and fenchone, its major component. BMC Complement Altern Med 17:347–359. https://doi.org/10.1186/s12906-017-1779-z
Roque VMN, Forones NM (2006) Avaliação da qualidade de vida e toxicidades em pacientes com câncer colorretal tratados com quimioterapia adjuvante baseada em fluoropirimidinas. Arq Gastroenterol 43(2):94–101
Sahebkar A (2011) Citrus auraptene: a potential multifunctional therapeutic agent for nonalcoholic fatty liver disease. Ann Hepatol 10(4):575–577
Sandhu S, Bansal Y, Silakari O, Bansal G (2014) Coumarin hybrids as novel therapeutic agents. Bioorg Med Chem 22:3806–3814. https://doi.org/10.1016/j.bmc.2014.05.032
Serban F, Artene SA, Georgescu AM, Purcaru SO, Tache DE, Alexandru O, Dricu A (2015) Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker. Onco Targets Ther 8:3767–3774. https://doi.org/10.2147/OTT.S93843
Siegel RL, Miller KD, Jemel A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442
Singh S, Dabur R, Gatne MM, Singh B, Gupta S, Pawar S, Sharma SK, Sharma GL, Andes DR (2014) In vivo efficacy of a synthetic coumarin derivative in a murine model of aspergillosis. PLoS ONE 9(8):e103039
Steger F, Hautmann MG, Kölbl OO (2012) 5-FU-induced cardiac toxicity-an underestimated problem in radiooncology? Radiat Oncol 7:212–216. https://doi.org/10.1186/1748-717X-7-212
Szczepanik AM, Siedlar M, Szura M, Kibil W, Brzuszkiewicz K, Brandt P, Kulig J (2015) Preoperative serum chemokine (C-C motif) ligand 2 levels and prognosis in colorectal cancer. Pol Arch Med Wewn 125(6):443–451
Tanaka S, Tatsuguchi A, Futagami S, Gudis K, Wada K, Seo T, Mitsui K, Yonezawa M, Nagata K, Fujimori S, Tsukui T, Kishida T, Sakamoto C (2006) Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma. Gut 55(1):54–61. https://doi.org/10.1136/gut.2004.059824
Thakur A, Singla R, Jaitak V (2015) Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem 101:476–495. https://doi.org/10.1016/j.ejmech.2015.07.010
Venugopala KN, Rashmi V, Odhav B (2013) Review on natural coumarin lead compounds for their pharmacological activity. Biomed Res Int 24:14–28. https://doi.org/10.1155/2013/963248
Vijay Avin BR, Thirusangu P, Lakshmi Ranganatha V, Firdouse A, Prabhakar BT, Khanum SA (2014) Synthesis and tumor inhibitory activity of novel coumarin analogs targeting angiogenesis and apoptosis. Eur J Med Chem 75:211–221. https://doi.org/10.1016/j.ejmech.2014.01.050
Wang SF, Yin Y, Wu X, Qiao F, Sha S, Lv PC, Zhao J, Zhu HL (2014) Synthesis, molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents. Bioorg Med Chem 22(21):5727–5737. https://doi.org/10.1016/j.bmc.2014.09.048
Wang YH, Liu YH, He GR, Lv Y, Du GH (2015) Esculin improves dyslipidemia, inflammation and renal damage in streptozotocin-induced diabetic rats. BMC Complement Altern Med 15:402–450. https://doi.org/10.1186/s12906-015-0817-y
World Health Organization (WHO) (2018) The top 10 causes of death. http://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed 09 October 2018
Xu G, Shi C, Guo D, Wang L, Ling Y, Han X, Luo J (2015) Functional-segregated coumarin-containing telodendrimer nanocarriers for efficient delivery of SN-38 for colon cancer treatment. Acta Biomater 21:85–98. https://doi.org/10.1016/j.actbio.2015.04.021
Yaghmaei S, Ghalayani P, Salami S, Nourmohammadian F, Koohestanimobarhan S, Imeni V (2017) Hybrid benzoxazole-coumarin compounds induce death receptor-mediated switchable apoptotic and necroptotic cell death on HN-5 head and neck cancer cell line. Anti Cancer Agents Med Chem 17(4):608–614
Ye X, Franco AA, Santos H, Nelson DM, Kaufman PD, Adams PD (2003) Defective S phase chromatin assembly causes DNA damage, activation of the S phase checkpoint, and S phase arrest. Mol Cell 11(2):341–351. https://doi.org/10.1016/S1097-2765(03)00037-6
Yu SM, Hu DH, Zhang JJ (2015) Umbelliferone exhibits anticancer activity via the induction of apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells. Mol Med Rep 12(3):3869–3873. https://doi.org/10.3892/mmr.2015.3797
Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001and CNPq.
Author information
Authors and Affiliations
Contributions
RMDC and JAFS conceived and designed the experiments; RMDC, TMB, TKGS, VMM, JAFS, RAA, RCF, FCL, MTB, and RCV performed the experiments; RMDC, JAFS, and MVS analyzed the data; FJBMJ and RSAA synthesized and provided the UMB-07; GCV performed the histopathological analysis; RMDC and MVS wrote the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
da Cruz, R.M.D., Batista, T.M., de Sousa, T.K.G. et al. Coumarin derivative 7-isopentenyloxycoumarin induces in vivo antitumor activity by inhibit angiogenesis via CCL2 chemokine decrease. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1701–1714 (2020). https://doi.org/10.1007/s00210-020-01884-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-020-01884-4