Abstract
Ginkgolic acids (GA), a group of alkyl phenols found in crude extracts of Ginkgo biloba leaves, are known to have anticancer activity, but their mode of action is not well understood. Our aim in this study was to investigate the anti-migratory activity of seven GA against breast cancer cells and to determine the molecular mechanism behind this activity. All seven GA and their mixture inhibited wound healing in MCF-7 and MDA-MB 231 breast cancer cells. None of the compounds nor the mixture showed cytotoxicity towards the two cell lines, if tested by the resazurin assay. C13:0 inhibited NF-κB activity in the HEK Blue Null 1 reporter cell line. Furthermore, C13:0 inhibited degradation of nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Sumoylation assay revealed that GA inhibited sumoylation of NF-κB essential modulator (NEMO). Molecular docking on SUMO-activating enzyme E1 showed that the seven GA bound to the active adenylation site with high calculated affinities ranging from -10.28 to -12.27 kcal/mol. Quantitative RT-PCR using C15:0, C13:0 and the mixture showed a significant down-regulation of urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9). We conclude that GA revealed considerable anti-migratory activity at non-cytotoxic concentrations, indicating anti-metastatic activity with low toxicity. This effect can be explained by the inhibition of NEMO sumoylation leading to inhibition of IκBα degradation and consequently a reduction of NF-κB activity, leading to the down-regulation of metastasis related genes including uPA, PAI-1, CXCR4, and MMP-9.
Highlights
Ginkgo biloba L. has been found in petrified fossils dating back more than 200 million years, and it is referred to as a living fossil [1]
This effect can be explained by the inhibition of NF-κB essential modulator (NEMO) sumoylation leading to inhibition of IκBα degradation and a reduction of NF-κB activity, leading to the down-regulation of metastasis related genes including urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), CXCR4, and matrix metalloproteinase 9 (MMP-9)
The Ginkgolic acids (GA) mixture showed the best activity. These results suggest that GA significantly suppressed the migration of breast cancer cells
Summary
Ginkgo biloba L. has been found in petrified fossils dating back more than 200 million years, and it is referred to as a living fossil [1]. The natural constituents of crude extracts of Ginkgo biloba include a group of alkyl phenols They are mainly ginkgolic acids (GA), cardanols (e.g. ginkgol), and cardols (e.g. bilobol), which are largely eliminated from the commercial preparation of Ginkgo biloba for safety reasons, as they have been reported to exhibit an allergenic and possibly a genotoxic potential. The alkyl phenols are eliminated during the multistep process www.impactjournals.com/oncotarget of the standardized EGb 761® preparation They are separated and removed from the primary acetone extract as insoluble compounds (decanter sludge) [10, 11]. These compounds are known to inhibit the enzymatic activity of lipoxygenase, cyclooxygenase, aldose reductase, glucosidase and tyrosinase. They reveal antimicrobial effects and may, protect the plant from damaging environmental effects [10]
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