Promising Candidate As An Anticancer Agent For Childhood, A Sesquiterpene Lactone: Dehydroleucodine
A Sesquiterpene Lactone: Dehydroleucodine
DOI:
https://doi.org/10.53555/bp.v7i12.1809Abstract
Objective: Despite emerging new treatments, there is a need for new anti-cancer agents for childhood solid tumors. Sesquiterpene lactones(SLs) are plant-derived secondary metabolites with anti-cancer properties. Dehydroleucodine(DhL) is a guaianolide-type SL isolated from Artemisia douglasiana (Asteraceae). In this study, the cytotoxic, antiproliferative, apoptotic effects of DhL on childhood solid tumors including Ewing sarcoma(ES), Hepatoblastoma(HBL), and Neuroblastoma(NB) were investigated in in-vitro conditions.
Material and Methods: In this study, NB cell line KELLY, ES cell line SK-ES-1, and HBL cell line Hep-G2 were used. Cell lines were cultured and LD50 doses of DhL and Cisplatin(CDDP) were calculated by MTT. Effective doses were applied to all cell lines, and percentages of apoptosis and necrosis were determined by Annexin V-PI test in flow cytometry. Morphological changes in cells were examined by toluidine blue staining. Immunocytochemical(ICC) examinations were performed with Caspase3,8, and 9 to determine the mechanism of apoptosis as Ki67 proliferation index. Statistical analysis was performed using the Mann-Whitney U test at a statistical significance level of p<0,05.
Results: LD50 doses of DhL and CDDP were determined as 75µM, 100µM for Kelly; 50µM, 100µM for HEP-G2; and 100µM, 300µM for SK-ES-1.
The intrinsic pathway in all cell lines was more pronounced in DhL, which reduced proliferation leading to apoptosis. DhL reduced proliferation less than CDDP and resulted in similar apoptotic cell death.
Conclusions: DhL showed a statistically significant anti-cancer activity similar to CDDP. It exerted this effect through apoptosis. Planning in-vivo experiments about this agent and explaining its molecular mechanisms, investigating the effects of other SL on childhood cancers are among our future goals.
Downloads
References
Bohlmann, F., Mahanta, P. K., Jakupovic, J., Rastogi, R. C. & Natu, A. A. New sesquiterpene lactones from Inula species. Phytochemistry (1978). doi:10.1016/S0031-9422(00)94308-5
Ren, Y., Yu, J. & Douglas Kinghorn, A. Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones. Curr. Med. Chem. 23, 2397–2420 (2016).
Chadwick, M., Trewin, H., Gawthrop, F. & Wagstaff, C. Sesquiterpenoids lactones: Benefits to plants and people. Int. J. Mol. Sci. 14, 12780–12805 (2013).
Ghantous, A., Gali-Muhtasib, H., Vuorela, H., Saliba, N. A. & Darwiche, N. What made sesquiterpene lactones reach cancer clinical trials? Drug Discov. Today 15, 668–678 (2010).
Zhang, Z. Y. et al. Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: A randomized controlled trial. J. Chinese Integr. Med. (2008). doi:10.3736/jcim20080206
Berger, T. G. et al. Artesunate in the treatment of metastatic uveal melanoma - First experiences. Oncol. Rep. (2005). doi:10.3892/or.14.6.1599
Singh, N. P. & Verma, K. B. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch. Oncol. (2002). doi:10.2298/AOO0204279S
Singh, N. P. & Panwar, V. K. Case report of a pituitary macroadenoma treated with artemether. Integr. Cancer Ther. (2006). doi:10.1177/1534735406295311
Zobalova, R. . et al. Drugs that kill cancer stem-like cells. Cancer Stem Cells Theor. Pract. 361–378 (2011). doi:10.5772/582
Tabata, K. et al. Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells. J. Pharmacol. Sci. 127, 397–403 (2015).
Costantino, V. V. et al. Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis. Cancer Lett. 372, 10–23 (2016).
Ordóñez, P. E. et al. Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells. J. Nat. Prod. 79, 691–696 (2016).
Priestap, H. A. et al. Dehydroleucodine and dehydroparishin-B inhibit proliferation and motility of B16 melanoma cells. Phytochem. Lett. 5, 581–585 (2012).
Bailon-Moscoso, N. et al. Phytometabolite Dehydroleucodine induces cell cycle arrest, apoptosis, and DNA damage in human astrocytoma cells through p73/p53 regulation. PLoS One 10, 1–18 (2015).
Stacey, G. N. Cancer Cell Culture, MTT assay. Methods Mol Biol 731, 79–91 (2011).
Hingorani, R., Deng, J., Elia, J., McIntyre, C. & Mittar, D. Detection of Apoptosis Using the BD Annexin V FITC Assay on the BD FACSVerseTM System. BD Biosci. August, 1–12 (2011).
Antigen, S., Method, R., Steps, B., Protocol, I. S. & Xt, V. D. Ihc ventana protocol. 1, 1–2
Shaloam, D. & Tchounwou, P. B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol. (2014). doi:10.1016/j.ejphar.2014.07.025.Cisplatin
Gach, K., Długosz, A. & Janecka, A. The role of oxidative stress in anticancer activity of sesquiterpene lactones. Naunyn. Schmiedebergs. Arch. Pharmacol. (2015). doi:10.1007/s00210-015-1096-3
Rüngeler, P. et al. Inhibition of transcription factor NF-κB by sesquiterpene lactones: A proposed molecular mechanism of action. Bioorganic Med. Chem. 7, 2343–2352 (1999).
Facts, C. Cancer Facts & Figures 2020. American Cancer Society (2020).
Stewart, E. et al. The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities. Dev. Biol. 411, 287–293 (2016).
Ward, E. & DeSantis, C. Childhood and Adolescent Cancer Statistics, 2014. 64, 83–103 (2014).
Sharma.et.al. Primary Ewing’s Sarcoma of Cranium in a Pediatric Patient. J. Pediatr. Neurosci. 273–5 (2017). doi:10.4103/jpn.JPN
Olgun, N. & Çeçen, E. Nöroblastom. Kanser Gündemi 4, 120 (2016).
Tabata, K. et al. Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells. J. Pharmacol. Sci. 127, 397–403 (2015).
Gach, K., Długosz, A. & Janecka, A. The role of oxidative stress in anticancer activity of sesquiterpene lactones. Naunyn. Schmiedebergs. Arch. Pharmacol. (2015). doi:10.1007/s00210-015-1096-3
Ordóñez, P. E. et al. Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells. J. Nat. Prod. 79, 691–696 (2016).
Priestap, H. A. et al. Dehydroleucodine and dehydroparishin-B inhibit proliferation and motility of B16 melanoma cells. Phytochem. Lett. 5, 581–585 (2012).
Bailon-Moscoso, N. et al. Phytometabolite Dehydroleucodine induces cell cycle arrest, apoptosis, and DNA damage in human astrocytoma cells through p73/p53 regulation. PLoS One 10, 1–18 (2015).
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2021 International Journal For Research In Biology & Pharmacy (ISSN: 2208-2093)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
In consideration of the journal, Green Publication taking action in reviewing and editing our manuscript, the authors undersigned hereby transfer, assign, or otherwise convey all copyright ownership to the Editorial Office of the Green Publication in the event that such work is published in the journal. Such conveyance covers any product that may derive from the published journal, whether print or electronic. Green Publication shall have the right to register copyright to the Article in its name as claimant, whether separately
or as part of the journal issue or other medium in which the Article is included.
By signing this Agreement, the author(s), and in the case of a Work Made For Hire, the employer, jointly and severally represent and warrant that the Article is original with the author(s) and does not infringe any copyright or violate any other right of any third parties, and that the Article has not been published elsewhere, and is not being considered for publication elsewhere in any form, except as provided herein. Each author’s signature should appear below. The signing author(s) (and, in
