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. 2015 Sep 2;10 Spec Iss(Spec Iss):227-40.
doi: 10.2147/IJN.S88289. eCollection 2015.

Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages

Abhishek Dubey  1 , Dae Won Park  2 , Jung Eun Kwon  2 , Yong Joon Jeong  2 , Taegeun Kim  1 , Inhye Kim  3 , Se Chan Kang  2 , Ki-Whan Chi  1
Affiliations

Investigation of the biological and anti-cancer properties of ellagic acid-encapsulated nano-sized metalla-cages

Abhishek Dubey et al. Int J Nanomedicine. .

Abstract

Three new large hexanuclear metalla-prisms 9-11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by (1)H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30 ± 0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein in macrophages.

Keywords: G-CSF; Rantes; antioxidant; metalla-prism; tumoricidal assay.

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Figures

Figure 1
Figure 1
(A) Synthesis of ellagic acid-encapsulated arene-ruthenium metalla-prisms 9–11 and (B) arene-ruthenium metalla-prisms 6–8.
Figure 2
Figure 2
Excerpts of 1H NMR spectra of (A) ellagic acid (5), (B) empty prism 6, (C) encapsulated prism 9, (D) empty prism 7, (E) encapsulated prism 10, (F) empty prism 8 and (G) encapsulated prism 11 in CD3NO2:CD3OD (1:1) solution. Abbreviation: ppm, parts per million.
Figure 3
Figure 3
Calculated (red) and experimental (black) ESI-MS spectra of ellagic acid encapsulated prisms 9–11. Abbreviation: ESI-MS, electrospray ionisation mass spectrometry.
Figure 4
Figure 4
UV/Vis spectra of ellagic acid (5), empty metalla-prisms 6–8 and ellagic acid-encapsulated metalla-prisms 9–11 in a solution of methanol (1×10−5 M). Abbreviation: UV/Vis, ultraviolet/visible.
Figure 5
Figure 5
Tumoricidal effects of ellagic acid (5) and compound 10 on co-cultured B16/F10 mouse skin carcinoma and RAW264.7 mouse macrophage cells. (A) Ellagic acid (5) and compound 10 without macrophage pretreatment. (B) Elicited macrophages pretreated with ellagic acid (5) and compound 10 24 hours before incubation with B16 cells. Notes: The results are mean ± SE of triplicates from a representative experiment. **P<0.01; significantly different from the control. Abbreviation: SE, standard error.
Figure 6
Figure 6
Plot showing the change in cytokine secretion of RAW264.7 macrophages with ellagic acid and compound 10. Abbreviations: TNF-α, tumor necrosis factor alpha; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; IL-6, interleukin-6; FGF6, fibroblast growth factor 6; IFNγ, interferon gamma; EGF, epidermal growth factor; IL-1α, interleukin-1alpha; IL-1β, interleukin-1beta; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1 alpha; SCF, Skp, cullin, F-box-containing complex; Rantes, regulated on activation, normal T cell expressed and secreted; PDGF, platelet-derived growth factor; β-NGF, beta-nerve growth factor; IL-17A, interleukin-17A; IL-2, interleukin-2; IL-4, interleukin-4; IL-10; interleukin-10.
Figure 7
Figure 7
Schematic representing the proposed events and G-CSF and Rantes gene expression in RAW264.7 macrophages with ellagic acid (control) and compound 10. Notes: The upward arrows indicate an increase in the G-CSF level and the crossed arrow indicates the inhibition of Rantes. Abbreviations: Rantes, regulated on activation normal T cell expressed and secreted; G-CSF, granulocyte-colony stimulating factor.
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