10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells

Evidence-Based Complementary and Alternative Medicine, Sep 2018

Vascular endothelial growth factor (VEGF) is reported to be a potent pro-angiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. Royal jelly (RJ) is a honeybee product containing various proteins, sugars, lipids, vitamins and free amino acids. 10-Hydroxy-2-decenoic acid (10HDA), a major fatty acid component of RJ, is known to have various pharmacological effects; its antitumor activity being especially noteworthy. However, the mechanism underlying this effect is unclear. We examined the effect of 10HDA on VEGF-induced proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Our findings showed that, 10HDA at 20 µM or more significantly inhibited such proliferation, migration and tube formation. Similarly, 10 µM GM6001, a matrix metalloprotease inhibitor, prevented VEGF-induced migration and tube formation. These findings indicate that 10HDA exerts an inhibitory effect on VEGF-induced angiogenesis, partly by inhibiting both cell proliferation and migration. Further experiments will be needed to clarify the detailed mechanism.

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10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells

10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-induced Angiogenesis in Human Umbilical Vein Endothelial Cells Hiroshi Izuta 0 Yuichi Chikaraishi 0 Masamitsu Shimazawa 0 Satoshi Mishima 1 Hideaki Hara 0 0 Department of Biofunctional Evaluation, Laboratory of Molecular Pharmacology, Gifu Pharmaceutical University , 5-6-1 Mitahora-higashi, Gifu 502-8585 , Japan 1 Nagaragawa Research Center, API Co. Ltd , 692-3 Nagara, Yamasaki, Gifu 502-0071 , Japan Vascular endothelial growth factor (VEGF) is reported to be a potent pro-angiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. Royal jelly (RJ) is a honeybee product containing various proteins, sugars, lipids, vitamins and free amino acids. 10-Hydroxy-2-decenoic acid (10HDA), a major fatty acid component of RJ, is known to have various pharmacological effects; its antitumor activity being especially noteworthy. However, the mechanism underlying this effect is unclear. We examined the effect of 10HDA on VEGFinduced proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs). Our findings showed that, 10HDA at 20 mM or more significantly inhibited such proliferation, migration and tube formation. Similarly, 10 mM GM6001, a matrix metalloprotease inhibitor, prevented VEGF-induced migration and tube formation. These findings indicate that 10HDA exerts an inhibitory effect on VEGF-induced angiogenesis, partly by inhibiting both cell proliferation and migration. Further experiments will be needed to clarify the detailed mechanism. HUVECs - migration - proliferation - tube formation Introduction Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is a highly regulated process that is essential for the development of multicellular organisms ( 1,2 ). In the adult, angiogenesis is normally restricted and is predominantly associated with female reproductive functions and wound healing ( 3,4 ). Vascular endothelial growth factor (VEGF) is a key regulator of normal and pathological angiogenesis ( 5?7 ). At the cellular level, VEGF stimulation drives multiple responses, including endothelial cell proliferation, migration, survival and permeability ( 8 ). Loss of regulation of angiogenesis, resulting in uncontrolled and excessive neovascularization, contributes to the development of many pathologies, including retinopathies, rheumatoid arthritis and tumor growth ( 9,10 ). Royal jelly (RJ), the exclusive food of the larva of the queen honeybee (Apis mellifera), is secreted from the hypopharyngeal and mandibular glands of the worker honeybees mainly between the sixth and twelfth days of their life ( 11 ). RJ has been demonstrated to possess several pharmacological activities in experimental animals, including vasodilator and hypotensive activities ( 12 ), growth rate increasing activity ( 13 ), a disinfectant action ( 14 ), antitumor activity ( 15?17 ), antihypercholesterolemic activity ( 18 ) and anti-inflammatory activity ( 19 ). Chemical composition analysis has shown that RJ consists mainly of proteins, sugars, lipids, vitamins and free amino acids ( 20,21 ). 10HDA, a major fatty acid component of RJ, has many pharmacological activities, such as antitumor activity (22), size- and lipogenesisinhibiting activity toward the hamster ear sebaceous gland ( 23 ), collagen production promoting activity ( 24 ) and antibiotic activity ( 25 ). As a consequence, RJ is widely used in commercial medical products, health foods and cosmetics in many countries. However, the mechanisms underlying these activities of RJ, especially the antitumor activity, remain unknown. Matrix metalloproteinase (MMP) is required for migration and invasion by normal and tumor cells. We initially utilized the MMP inhibitor GM6001 to assess the effect of MMP inhibitors on thymocyte development. GM6001, a hydroxylamine-based inhibitor which inhibits many MMP with a Ki in the low nanomolar range, has been reported to reduce the migration of many kinds of cells ( 26 ). We used GM6001 as a positive control in the present study. The purpose here was to evaluate the functional role of 10HDA on human pathology. A number of compounds, including valproic acid ( 27 ), sodium butyrate ( 28 ) and isomers of conjugated linoleic acid ( 29 ), are known to be angiogenesis inhibitors. Here, we examined the effects of 10HDA on VEGF-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Methods Cells and Chemicals HUVECs, fibroblast cells, endothelial cell basal medium (HuMedia-EB2), fetal bovine serum (FBS), gentamycin, amphotericin B, endothelial growth factors (hEGF, hydrocortisone, hFGF-B and heparin), VEGF, mouse antihuman CD31 antibody, goat antimouse IgG alkaline phosphatase-conjugated antibody, 5-bromo-4-chloro3-indolyl phosphate/nitro blue tetrazolium (BCIP/NBT) and angiogenesis growth medium were purchased from Kur (...truncated)


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Hiroshi Izuta, Yuichi Chikaraishi, Masamitsu Shimazawa, Satoshi Mishima, Hideaki Hara. 10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells, Evidence-Based Complementary and Alternative Medicine, 6, DOI: 10.1093/ecam/nem152