Abstract
Natural products have played a pivotal role for the discovery of anticancer drugs. Tonantzitlolones are flexibilan-type diterpenes rare in nature; therefore, few reports have shown antiviral and cytotoxic activities. This study aimed to investigate the in vivo antitumor action of Tonantzitlolone B (TNZ-B) and its toxicity. Toxicity was evaluated in mice (acute and micronucleus assays). Antitumor activity of TNZ-B (1.5 or 3 mg/kg intraperitoneally — i.p.) was assessed in Ehrlich ascites carcinoma model. Angiogenesis and reactive oxygen species (ROS) and nitric oxide (NO) production were also investigated, in addition to toxicological effects after 7-day treatment. The LD50 (lethal dose 50%) was estimated at around 25 mg/kg (i.p.), and no genotoxicity was recorded. TNZ-B reduced the Ehrlich tumor’s volume and total viable cancer cell count (p < 0.001 for both). Additionally, TNZ-B reduced peritumoral microvessel density (p < 0.01), suggesting antiangiogenic action. Moreover, a decrease was observed on ROS (p < 0.05) and nitric oxide (p < 0.001) levels. No significant clinical findings were observed in the analysis of biochemical, hematological, and histological (liver and kidney) parameters. In conclusion, TNZ-B exerts antitumor and antiangiogenic effects by reducing ROS and NO levels and has weak in vivo dose-repeated toxicity. These data contribute to elucidate the antitumor action of TNZ-B and point the way for further studies with this natural compound as an anticancer drug.
This is a preview of subscription content, log in via an institution to check access.
Data availability
Data available on request.
Code availability
Not applicable.
References
Abreu LS, Nascimento YM, Costa RS, Guedes MLS, Souza BNRF, Pena LJ, Costa VCO, Scotti MT, Braz-Filho R, Barbosa-Filho JM, Silva MS, Velozo ES, Tavares JF (2019) Tri- and diterpenoids from Stillingia loranthacea as inhibitors of Zika virus replication. J Nat Prod 82(10):2721–2730. https://doi.org/10.1021/acs.jnatprod.9b00251
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 Farmacogn 80:72–76
Auletta CS (1995) Acute, subchronic, and chronic toxicology. In: Handbook of toxicology, Derelanko HJ, Hollinger MA (Eds) CRC Press, London, pp. 51–162. https://doi.org/10.1002/food.19960400524
Busch T, Dräger G, Kunst E, Benson H, Sasse F, Siems K, Kirschning A (2016) Synthesis and antiproliferative activity of new tonantzitlolone-derived diterpene derivatives. Org Biomol Chem 14(38):9040–9045. https://doi.org/10.1039/C6OB01697A
Busch T, Schuster H, Kirschning A (2008) Determination of the absolute configuration of the diterpene Tonantzitlolone B. Tetrahedron Lett 49(36):5273–5275. https://doi.org/10.1016/j.tetlet.2008.06.105
Cheng H, Wang L, Mollica M, Re AT, Wu S, Zuo L (2014) Nitric oxide in cancer metastasis. Cancer Lett 353(1):1–7. https://doi.org/10.1016/j.canlet.2014.07.014
Cruz RMD, Batista TM, de Sousa TKG, Mangueira VM, Santos JAF, Abrantes RA, Ferreira RC, Leite FC, Brito MT, Batista LM, Veras RC, Vieira GC, Mendonca-Jr FJB, Araújo RSA (2020) Sobral MV (2020) Coumarin derivative 7-isopentenyloxycoumarin induces in vivo antitumor activity by inhibit angiogenesis via CCL2 chemokine decrease. Naunyn-Schmiedeberg’s Arch Pharmacol 393:1701–1714. https://doi.org/10.1007/s00210-020-01884-4
Dräger G, Jeske F, Kunst E, Lopez EG, Sanchez HV, Tsichritzis F, Kirschning A, Jakupovic J (2007) Tonantzitlolone and other diterpenes from Stillingia sanguinolenta. Eur J Org Chem: 5020−5026. https://doi.org/10.1002/ejoc.200701071
Fukai T, Ushio-Fukai M (2020) Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells 9(8):1849. https://doi.org/10.3390/cells9081849
Galadari S, Rahman A, Pallichankandy S, Thayyullathil F (2017) Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med 104:144–164. https://doi.org/10.1016/j.freeradbiomed.2017
Gaspar BL, Sharma P, Das R (2015) Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology 20:18–25. https://doi.org/10.1179/1607845414Y.0000000161
Ghauri MA, Su Q, Ullah A, Wang J, Sarwar A, Wu Q, Zhang D, Zhang Y (2021) Sanguinarine impedes metastasis and causes inversion of epithelial to mesenchymal transition in breast cancer. Phytomedicine 84:153500. https://doi.org/10.1016/j.phymed.2021.153500
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138. https://doi.org/10.1016/0003-2697(82)90118-x
Guan Y-Y, Luan X, Lu Q, Liu Y-R, Sun P, Zhao M, Chen H-Z, Fang C (2016) Natural products with antiangiogenic and antivasculogenic mimicry activity. Mini Rev Med Chem 16:1290–1302. https://doi.org/10.2174/1389557516666160211115507
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013
Hu Y, Xiang J, Su L, Tang X (2020) The regulation of nitric oxide in tumor progression and therapy. J Int Med Res 48(2):1–9. https://doi.org/10.1177/0300060520905985
Moloney JN, Cotter TG (2018) ROS signalling in the biology of cancer. Semin Cell Dev Biol 80:50–64. https://doi.org/10.1016/j.semcdb.2017.05.023
Newman DJ, Cragg GM (2020) Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 83(3):770–803. https://doi.org/10.1021/acs.jnatprod.9b01285
Novillo F, Rosero V, Chávez MI, Hernández-Ortega S, Martínez EM, Delgado G (2017) Tonantzitlolone A and other cytotoxic constituents of Sapium macrocarpum (Euphorbiaceae). J Mex Chem Soc 61(1):67–73. https://doi.org/10.29356/jmcs.v61i1.130
Olivon F, Palenzuela H, Girard-Valenciennes E, Neyts J, Pannecouque C, Roussi F, Grondin I, Leyssen P, Litaudon M (2015) Antiviral activity of flexibilane and tigliane diterpenoids from Stillingia lineata. J Nat Prod 78(5):1119–1128. https://doi.org/10.1021/acs.jnatprod.5b00116
Organisation for Economic Co-operation and Development (OECD), Guideline for testing of chemicals n. 423: acute oral toxicity, OECD, Paris, 2001, pp. 1–14
Organisation for Economic Co-operation and Development (OECD), Guideline for testing of chemicals n. 474: mammalian erythrocyte micronucleus test, OECD, Paris, 2016, pp. 1–21
Pfeffer TJ, Sasse F, Schmidt CF, Lakämper S, Kirschning A, Scholz T (2016) The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function. Eur J Med Chem 112:164–170. https://doi.org/10.1016/j.ejmech.2016.02.022
Pita JCLR, Xavier AL, Sousa TKG, Mangueira VM, Tavares JF, Júnior RJO, Veras RC, Pessoa HLF, Silva MS, Morelli S, Ávila VMR, Silva TG, Diniz MFFM, Castello-Branco MVS (2012) In vitro and in vivo antitumor effect of trachylobane-360, a diterpene from Xylopia langsdorffiana. Molecules 17(8):9573–9589. https://doi.org/10.3390/molecules17089573
Qiang H, Chang Q, Xu J, Qian J, Zhang Y, Lei Y, Han B, Chu T (2020) New advances in antiangiogenic combination therapeutic strategies for advanced non-small cell lung cancer. J Cancer Res Clin Oncol 146:631–645. https://doi.org/10.1007/s00432-020-03129-6
Rajabi M, Mousa S (2017) The role of angiogenesis in cancer treatment. Biomedicines 5(4):34. https://doi.org/10.3390/biomedicines5020034
Ribeiro A, Abreu RMV, Dias MM, Barreiro MF, Ferreira ICFR (2018) Antiangiogenic compounds: well-established drugs versus emerging natural molecules. Cancer Lett 415:86–105. https://doi.org/10.1016/j.canlet.2017.12.006
Ridnour LA, Isenberg JS, Espey MG, Thomas DD, Roberts DD, Wink DA (2005) Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc Natl Acad Sci USA 102(37):13147–13152. https://doi.org/10.1073/pnas.0502979102
Rubaiy HN (2019) Treasure troves of pharmacological tools to study TRPC1/4/5 channels. Br J Pharmacol 176:832–846. https://doi.org/10.1111/bph.14578
Rubaiy HN, Ludlow MJ, Siems K, Norman K, Foster R, Wolf D, Beutler JA, Beech DJ (2018) Tonantzitlolone is a nanomolar potency activator of transient receptor potential canonical 1/4/5 channels. Br J Pharmacol 175(16):3361–3368. https://doi.org/10.1111/bph.14379
Santos J, Brito M, Ferreira R, Moura A, Sousa T, Batista T, Mangueira V, Leite F, Cruz R, Vieira G, Lira B, Athayde-Filho P, Souza H, Costa N, Veras R, Barbosa-Filho JM, Magalhães H, Sobral M (2018) Th1-biased immunomodulation and in vivo antitumor effect of a novel piperine analogue. Int J Mol Sci 19(9):2594. https://doi.org/10.3390/ijms19092594
Sommer S, Buraczewska I, Kruszewski M (2020) Micronucleus assay: the state of art, and future directions. Int J Mol Sci 21(4):1534. https://doi.org/10.3390/ijms21041534
Sourbier C, Scroggins BT, Mannes PZ, Liao P-J, Siems K, Wolf D, Beutler JA, Linehan WM, Neckers L (2015) Tonantzitlolone cytotoxicity toward renal cancer cells is PKCθ- and HSF1-dependent. Oncotarget 6(30):29963–29974. https://doi.org/10.18632/oncotarget.4676
Tae N, Hung TM, Kim O, Kim N, Lee S, Na S, Min B-S, Lee J-H (2017) A cassaine diterpene alkaloid, 3β-acetyl-nor-erythrophlamide, suppresses VEGF-induced angiogenesis and tumor growth via inhibiting eNOS activation. Oncotarget 8(54):92346–92358. https://doi.org/10.18632/oncotarget.21307
Techer S, Girard-Valenciennes E, Retailleau P, Neyts J, Guéritte F, Leyssen P, Litaudon M, Smadja J, Grondin I (2015) Tonantzitlolones from Stillingia lineata ssp. lineata as potential inhibitors of chikungunya virus. Phytochem Lett 12:313–319. https://doi.org/10.1016/j.phytol.2015.04.023
Tousson E, Hafez E, Abo Gazia MM, Salem SB, Mutar TF (2020) Hepatic ameliorative role of vitamin B17 against Ehrlich ascites carcinoma–induced liver toxicity. Environ Sci Pollut Res. https://doi.org/10.1007/s11356-019-06528-6
Vedenko A, Panara K, Goldstein G, Ramasamy R, Arora H (2020) Tumor microenvironment and nitric oxide: concepts and mechanisms. In: Tumor microenvironment. Advances in Experimental Medicine and Biology. Birbrair A (Eds) Springer, Cham, vol 1277, pp 143–158. https://doi.org/10.1007/978-3-030-50224-9_10
Wardana AP, Aminah NS, Rosyda M, Abdjan MI, Kristanti AN, Tun KNW, Choudhary MI, Takaya Y (2021) Potential of diterpene compounds as antivirals, a review. Heliyon 7(8):e07777. https://doi.org/10.1016/j.heliyon.2021.e07777
Mohanad, Zbidah Adrian, Lupescu Tabea, Herrmann Wenting, Yang Michael, Foller Kashif, Jilani Florian, Lang (2013) Effect of honokiol on erythrocytes. Toxicology in Vitro 27(6) 1737-1745 10.1016/j.tiv.2013.05.003
Zbidah M, Lupescu A, Herrmann T, Yang W, Foller M, Jilani K, Lang F (2013) Effect of honokiol on erythrocytes. Toxicol in Vitro 27:1737–1745. https://doi.org/10.1016/j.tiv.2013.05.003
Funding
Pharmaceuticals and Medicines Research Institute—Federal University of Paraíba (IPeFarM/UFPB); The Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001 and CNPq partly financed this study.
Author information
Authors and Affiliations
Contributions
RAA and MVS conceived and designed the experiments; RAA, TMB, VMM, TKGS, RCF, and APGM conducted experiments; RAA, LMB, and MVS analyzed data; LSB, ESV, JFT, and MSS isolated and provided the TNZ-B; AFA performed the histopathological analysis; RAA and MVS wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
Corresponding author
Ethics declarations
Ethics approval
All experiments were carried out in accordance with the standards established by the Brazilian Society of Science in Laboratory Animal (SBCAL) and with the standards established by the National Institute of Health Guide for Care and Use of Laboratory Animals. Experimental procedures were approved by the Ethical Committee on the Use of Animals of the Federal University of Paraíba (CEUA)/UFPB (n. 112/2017).
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
de Abrantes, R.A., Batista, T.M., Mangueira, V.M. et al. Antitumor and antiangiogenic effects of Tonantzitlolone B, an uncommon diterpene from Stillingia loranthacea. Naunyn-Schmiedeberg's Arch Pharmacol 395, 267–274 (2022). https://doi.org/10.1007/s00210-021-02185-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-021-02185-0