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Evidence-Based Complementary and Alternative Medicine Volume 2019 ,2019-03-03
Cytotoxic and Apoptotic Activity of Majoranolide from Mezilaurus crassiramea on HL-60 Leukemia Cells
Research Article
Lanna M. Heemann 1 Kamylla F. S. de Souza 1 Danilo Tófoli 2 Kelly J. Filippin 1 Walmir S. Garcez 2 Maria de Fatima C. Matos 1 Fernanda R. Garcez 2 Renata T. Perdomo 1
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Received 2018-11-26, accepted for publication 2019-02-10, Published 2019-02-10

Majoranolide, a butanolide isolated from the nonpolar fraction of an ethanol extract of Mezilaurus crassiramea (Lauraceae) fruits, is being reported for the first time in this genus and the third time in plants. Structurally identified from 1D and 2D NMR and HRESIMS data, majoranolide proved cytotoxic against cancer cells—MCF-7 and MDA-MB-231 (breast), HT-29 (colon), PC-3 (prostate), 786-0 (renal), and HL-60 (leukemia)—inhibiting growth in HL-60 cells (GI50 = 0.21 μM) and exhibiting higher selectivity for this line than for nonneoplastic NIH/3T3 murine fibroblasts. Effects on the cell cycle, caspase-3 activation, and plasma membrane integrity were evaluated by flow cytometry. Expression of genes related to apoptotic pathways (BAX, BCL2, BIRC5, and CASP8) was investigated using RT-qPCR. At 50 μM, majoranolide induced cell cycle arrest at G1 in 24 h increased the sub-G1 population in 48 h and increased caspase-3 activation in a time-dependent manner. The compound upregulated BAX and CASP8 transcription (proapoptotic genes) and downregulated BIRC5 (antiapoptotic). Loss of plasma membrane integrity in 30% of cells occurred at 48 h, but not at 24 h, characterizing gradual, programmed death. The results suggest that majoranolide cytotoxicity involves apoptosis induction in HL-60 cells, although other mechanisms may contribute to this cell death.


Copyright © 2019 Lanna M. Heemann et al. 2019
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Renata T. Perdomo.Laboratory of Molecular Biology and Cell Culture, School of Pharmaceutical Sciences, Food Technology, and Nutrition, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil, ufms.br.renataperdomo@gmail.com


Lanna M. Heemann,Kamylla F. S. de Souza,Danilo Tófoli,Kelly J. Filippin,Walmir S. Garcez,Maria de Fatima C. Matos,Fernanda R. Garcez,Renata T. Perdomo. Cytotoxic and Apoptotic Activity of Majoranolide from Mezilaurus crassiramea on HL-60 Leukemia Cells. Evidence-Based Complementary and Alternative Medicine ,Vol.2019(2019)



[1] T. Mosmann. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods.65(1-2):55-63. DOI: 10.1590/S1676-06032005000300018.
[2] A. Monks, D. Scudiero, P. Skehan, R. Shoemaker. et al.(1991). Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Journal of the National Cancer Institute.83(11):757-766. DOI: 10.1590/S1676-06032005000300018.
[3] P. Bouwman, J. Jonkers. (2012). The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nature Reviews Cancer.12(9):587-598. DOI: 10.1590/S1676-06032005000300018.
[4] H. Li, H. Zhu, C. Xu, J. Yuan. et al.(1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell.94(4):491-501. DOI: 10.1590/S1676-06032005000300018.
[5] R. H. Shoemaker. (2006). The NCI60 human tumour cell line anticancer drug screen. Nature Reviews Cancer.6(10):813-823. DOI: 10.1590/S1676-06032005000300018.
[6] P. Houghton, R. Fang, I. Techatanawat, G. Steventon. et al.(2007). The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity. Methods.42(4):377-387. DOI: 10.1590/S1676-06032005000300018.
[7] H.-S. Chang, I.-S. Chen. (2016). Chemical constituents and bioactivity of Formosan lauraceous plants. Journal of Food and Drug Analysis.24(2):247-263. DOI: 10.1590/S1676-06032005000300018.
[8] S.-Y. Chang, M.-J. Cheng, C.-F. Peng, H.-S. Chang. et al.(2008). Antimycobacterial butanolides from the root of Lindera akoensis. Chemistry & Biodiversity.5(12):2690-2698. DOI: 10.1590/S1676-06032005000300018.
[9] A. Kamb, S. Wee, C. Lengauer. (2007). Why is cancer drug discovery so difficult?. Nature Reviews Drug Discovery.6(2):115-120. DOI: 10.1590/S1676-06032005000300018.
[10] H.-M. Wang, C.-C. Chiu, P.-F. Wu, C.-Y. Chen. et al.(2011). Subamolide E from Cinnamomum subavenium induces sub-G1 cell-cycle arrest and caspase-dependent apoptosis and reduces the migration ability of human melanoma cells. Journal of Agricultural and Food Chemistry.59(15):8187-8192. DOI: 10.1590/S1676-06032005000300018.
[11] F. R. Garcez, W. S. Garcez, M. Martins, M. F. C. Matos. et al.(2005). Cytotoxic and genotoxic butanolides and lignans from Aiouea trinervis. Planta Medica.71(10):923-927. DOI: 10.1590/S1676-06032005000300018.
[12] W.-W. Ma, J. E. Anderson, C.-J. Chang, D. L. Smith. et al.(1990). Majoranolide: a -lactone from. Phytochemistry.29(8):2698-2699. DOI: 10.1590/S1676-06032005000300018.
[13] J. Chen. (2016). The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harbor Perspectives in Medicine.6(3). DOI: 10.1590/S1676-06032005000300018.
[14] L. Galluzzi, I. Vitale, J. M. Abrams, E. S. Alnemri. et al.(2012). Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death & Differentiation.19(1):107-120. DOI: 10.1590/S1676-06032005000300018.
[15] T. Miyashita, J. C. Reed. (1995). Tumor suppressor p53 is a direct transcriptional activator of the human gene. Cell.80(2):293-299. DOI: 10.1590/S1676-06032005000300018.
[16] B. M. Fraga, D. Terrero. (1996). Alkene--lactones and avocadofurans from Persea indica: A revision of the structure of majorenolide and related lactones. Phytochemistry.41(1):229-232. DOI: 10.1590/S1676-06032005000300018.
[17] H.-M. D. Wang, C.-Y. Chen, P.-F. Wu. (2014). Isophilippinolide a arrests cell cycle progression and induces apoptosis for anticancer inhibitory agents in human melanoma cells. Journal of Agricultural and Food Chemistry.62(5):1057-1065. DOI: 10.1590/S1676-06032005000300018.
[18] C. Holohan, S. van Schaeybroeck, D. B. Longley, P. G. Johnston. et al.(2013). Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer.13(10):714-726. DOI: 10.1590/S1676-06032005000300018.
[19] V. L. Almeida, A. Leitão, L. D. Reina, C. A. Montanari. et al.(2005). Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: uma introdução. Química Nova.28(1):118-129. DOI: 10.1590/S1676-06032005000300018.
[20] A. Albrecht, J. F. Koszuk, J. Modranka, M. Rózalski. et al.(2008). Synthesis and cytotoxic activity of -aryl substituted -alkylidene--lactones and -alkylidene--lactams. Bioorganic & Medicinal Chemistry.16(9):4872-4882. DOI: 10.1590/S1676-06032005000300018.
[21] I.-L. Tsai, C.-H. Hung, C.-Y. Duh, I.-S. Chen. et al.(2002). Cytotoxic butanolides and secobutanolides from the stem wood of Formosan Lindera communis. Planta Medica.68(2):142-145. DOI: 10.1590/S1676-06032005000300018.
[22] O. Kepp, L. Galluzzi, M. Lipinski, J. Yuan. et al.(2011). Cell death assays for drug discovery. Nature Reviews Drug Discovery.10(3):221-237. DOI: 10.1590/S1676-06032005000300018.
[23] N. Singh, S. Krishnakumar, R. K. Kanwar, C. H. A. Cheung. et al.(2015). Clinical aspects for survivin: A crucial molecule for targeting drug-resistant cancers. Drug Discovery Therapy.20(5):578-587. DOI: 10.1590/S1676-06032005000300018.
[24] A. Dasgupta, M. Nomura, R. Shuck, J. Yustein. et al.(2016). Cancer’s achilles’ heel: Apoptosis and necroptosis to the rescue. International Journal of Molecular Sciences.18(1):23. DOI: 10.1590/S1676-06032005000300018.
[25] D. Tófoli, L. Martins, M. Matos, W. Garcez. et al.(2016). Antiproliferative Butyrolactones from Mezilaurus crassiramea. Planta Medica Letters.3(01):e14-e16. DOI: 10.1590/S1676-06032005000300018.
[26] A. Letai. (2017). Apoptosis and cancer. Annual Review of Cancer Biology.1(1):275-294. DOI: 10.1590/S1676-06032005000300018.
[27] P. Skehan, R. Storeng, D. Scudiero, A. Monks. et al.(1990). New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute.82(13):1107-1112. DOI: 10.1590/S1676-06032005000300018.
[28] P. L. Moraes. (2005). Sinopse das Lauráceas nos estados de Goiás e Tocantins, Brasil. Biota Neotropica.5(2):253-270. DOI: 10.1590/S1676-06032005000300018.
[29] M. Kajstura, H. D. Halicka, J. Pryjma, Z. Darzynkiewicz. et al.(2007). Discontinuous fragmentation of nuclear DNA during apoptosis revealed by discrete 'sub-G1' peaks on DNA content histograms. Cytometry Part A: The journal of the International Society for Analytical Cytology.71(3):125-131. DOI: 10.1590/S1676-06032005000300018.
[30] A. Zhang, Y. Sheng, M. Zou. (2017). Antiproliferative activity of Alisol B in MDA-MB-231 cells is mediated by apoptosis, dysregulation of mitochondrial functions, cell cycle arrest and generation of reactive oxygen species. Biomedicine & Pharmacotherapy.87:110-117. DOI: 10.1590/S1676-06032005000300018.
[31] G. Ichim, S. W. G. Tait. (2016). A fate worse than death: apoptosis as an oncogenic process. Nature Reviews Cancer.16(8):539-548. DOI: 10.1590/S1676-06032005000300018.
[32] R. S. Y. Wong. (2011). Apoptosis in cancer: from pathogenesis to treatment. Journal of Experimental & Clinical Cancer Research.30(1):87. DOI: 10.1590/S1676-06032005000300018.
[33] I.-S. Chen, I.-L. Lai-Yaun, C.-Y. Duh, I.-L. Tsai. et al.(1998). Cytotoxic butanolides from Litsea akoensis. Phytochemistry.49(3):745-750. DOI: 10.1590/S1676-06032005000300018.
[34] C. Burz, I. Berindan-Neagoe, O. Balacescu, A. Irimie. et al.(2009). Apoptosis in cancer: key molecular signaling pathways and therapy targets. Acta Oncologica.48(6):811-821. DOI: 10.1590/S1676-06032005000300018.
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