Abstract
Objective
To synthesize and determine the antitumor activity of 10-chlorocanthin-6-one in ovarian cancer HO8910PM cells.
Results
Among the synthesized canthin-6-one analogs, 10-chlorocanthin-6-one was the most cytotoxic (IC50 = 4.9 μM), as demonstrated by a dose-dependent cytotoxicity assay. Moreover, 10-chlorocanthin-6-one induced apoptosis through the activation of poly(ADP-ribose) polymerase and caspase-3 cleavage, upregulation of Bcl-2, and downregulation of Bim, x-linked inhibitor of apoptosis protein (XIAP), and survivin in HO8910PM cells. Furthermore, Bim RNA, upregulated in a concentration-dependent manner, and knockdown of Bim via short-hairpin RNAs attenuated the inhibitory effects of 10-chlorocanthin-6-one on HO8910PM cell growth.
Conclusions
10-Chlorocanthin-6-one inhibits cell proliferation and induces apoptosis in H08910PM cells. The underlying molecular mechanisms of 10-chlorocanthin-6-one include activation of the Bim-mediated mitochondrial apoptotic pathway via upregulation of Bim and downregulation of Bcl-2, XIAP, and survivin. These data suggest that Bim is a potential target of 10-chlorocanthin-6-one, further demonstrating its potential use in the prevention and treatment of ovarian cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
29 December 2017
The addresses given for the authors of this paper were incorrect. The correct assignments of the authors are given in this erratum.
References
Akiyama T, Dass CR, Choong PF (2009) Bim-targeted cancer therapy: a link between drug action and underlying molecular changes. Mol Cancer Ther 8:3173–3180
Andreas G, Panayiotis AK (2010) Two-step total syntheses of canthin-6-one alkaloids: new one-pot sequential Pd-catalyzed Suzuki-Miyaura coupling and Cu-catalyzed amidation reaction. Org Lett 12:1352–1355
Anupam B, Gautam S (2016) Bioactive natural products in cancer prevention and therapy: progress and promise. Semin Cancer Biol 40–41:1–3
Devkota KP, Wilson JA, Henrich CJ, McMahon JB, Reilly KM, Beutler JA (2014) Compounds from Simarouba berteroana which inhibit proliferation of NF1-defective cancer cells. Phytochem Lett 7:42–45
Diab Y, Muallem MZ (2017) Targeted therapy in ovarian cancer. A comprehensive systematic review of literature. Anticancer Res 37:2809–2815
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD (2008) BAX activation is initiated at a novel interaction site. Nature 455:1076–1081
Ghosh B, Antonio T, Reith MEA, Dutta AK (2010) Discovery of 4-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: in vivo activity indicates potential application in symptomatic and neuroprotective therapy for parkinson’s disease. J Med Chem 53:2114–2125
Gillings AS, Balmanno K, Wiggins CM, Johnson M, Cook SJ (2009) Apoptosis and autophagy: BIM as a mediator of tumor cell death in response to oncogene-targeted therapeutics. FEBS J 276:6050–6062
Haynes HF, Nelson ER, Price JR (1948) Alkaloids of the Australian Rutaceae. Nature 162:223
Landy A (1989) Dynamic, structural and regulatory aspects of lambda site-specific recombination. Annu Rev Biochem 58:913–949
Martin Lluesma S, Wolfer A, Harari A, Kandalaft LE (2016) Cancer vaccines in ovarian cancer: how can we improve? Biomedicines 4:3–10
Qi FH, Wang ZX, Cai PP, Zhao L, Gao JJ, Kokudo N, Li AY, Han JQ, Tang W (2013) Traditional Chinese medicine and related active compounds: a review of their role on hepatitis B virus infection. Drug Discov Ther 7:212–224
Rehman SU, Choe K, Yoo HH (2016) Review on a traditional herbal medicine, Eurycoma longifolia Jack (Tongkat Ali): its traditional uses, chemistry, evidence-based pharmacology and toxicology. Molecules 21:331
Remy M, Georges P, Pascal B, Frederic J, Maryannick L, Mickael M, Patrick P (2008) Strategic studies in the syntheses of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones. Tetrahedron 64:2772–2782
Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29
Soriano-Agatón F, Lagoutte D, Poupon E, Roblot F, Fournet A, Gantier JC, Hocquemiller R (2005) Extraction, hemisynthesis, and synthesis of canthin-6-one analogues. Evaluation of their antifungal activities. Nat Prod 68:1581–1587
Tang Y, Simoneau AR, Xie J, Shahandeh B, Zi X (2008) Effects of the kava chalcone flavokawain A differ in bladder cancer cells with wild-type versus mutant p53. Cancer Prev Res 1:439–451
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108
Yan WJ, Wang Q, Yuan CH, Wang F, Ji Y, Dai F, Jin XL, Zhou B (2016) Designing piperlongumine-directed anticancer agents by an electrophilicity-based pro-oxidant strategy: a mechanistic investigation. Free Radic Biol Med 97:109–123
Acknowledgements
This study was financially supported by the National Natural Science Foundation of China # 81573662 (Yaxiong Tang) and the International Cooperation Program of SiChuan, China # 2015HH048 (Yaxiong Tang).
Supporting information
1. Procedures for the preparation of 10-chlorocanthin-6-one.
2. Spectroscopic data of 10-chlorocanthin-6-one.
Author information
Authors and Affiliations
Corresponding author
Additional information
A correction to this article is available online at https://doi.org/10.1007/s10529-017-2496-x.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, W., Chen, Y., Sheng, Y. et al. Synthesis and inhibitory effect of 10-chlorocanthin-6-one on ovarian cancer HO8910PM cells. Biotechnol Lett 40, 23–30 (2018). https://doi.org/10.1007/s10529-017-2438-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10529-017-2438-7