6″-Debromohamacanthin A, a Bis (Indole) Alkaloid, Inhibits Angiogenesis by Targeting the VEGFR2-Mediated PI3K/AKT/mTOR Signaling Pathways

Abstract

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…bisacetylenic alcohol ( 191 ) [184]; conicasterol E ( 192 ) [185]; 6”-debromohamacanthin A ( 193 ) [186]; dieckol ( 194 ) [187]; fructigenine A ( 195 ) [188]; geoditin A ( 196 ) [189]; gorgosterol ( 197 ) [190]; gracilioether B ( 198 ) [191]; gracilioether K ( 199 ) [192]; herdmanine K ( 200 ) [193]; hyrtioreticulin A ( 201 ) [194]; new Kunitz-type protease inhibitor InHVJ ( 202 ) [195]; jaspamide ( 203 ) [196]; latonduine A ( 204 ) [197]; leucettine L41 ( 205 ) [169]; manzamine A ( 206 ) [198]; nahuoic acid A ( 207 ) [199]; namalide ( 208 ) [200]; ningalins C and D ( 209 , 210 ) [201]; octaphlorethol A ( 114 ) [120]; petrosaspongiolide M ( 211 ) [202]; petrosiol A ( 212 ) [203]; phidianidine A ( 213 ) [204]; Poly-APS ( 214 ) [205]; Pseudoceratina sp. dibromotyrosine ( 215 ) [206]; pseudopterosin A ( 216 ) [207]; sargachromanol G ( 217 ) [208]; S. graminifolium polysaccharide ( 218 ) [209]; S. patens phloroglucinol ( 219 ) [210]; S. xiamenensis benzopyran ( 220 ) [211]; theonellasterol ( 221 ) [212]; toluquinol ( 222 ) [213]; and U. lactuca fatty acid ( 223 ) [214].…”

Plants and their active compounds: natural molecules to target angiogenesis

“…In addition, brucine also inhibited VEGF, nitric oxide (NO), IL-6, IL-8, TNF-α and IFN-γ in human umbilical vein cells [73]. Another indole alkaloid, 6′-debromohamacanthin A, which is found in marine sponges, and tylophorine, a phenanthroindolizidine alkaloid isolated from Tylophora indica , inhibited VEGF and VEGFR-2 mediated-angiogenesis at a concentration of ≤10 μM via similar mechanisms through the PI3K/Akt/mTOR signaling pathway [74, 75]. Furthermore, norisoboldine, an alkaloid isolated from Radix Linderae , demonstrated Notch1-mediated anti-angiogenic effects in an experimental rheumatoid arthritis model at a dose of 7.5 mg/kg [76].…”

Acetylcholinesterase inhibitory dimeric indole derivatives from the marine actinomycetes Rubrobacter radiotolerans

“…Indole derivatives derived from marine invertebrates exhibit diverse and potent bioactivities, such as antioxidant; PLA2 (phospholipase A2) inhibition activity; antimicrobial activity; anti-angiogenic effect; anti-inflammtory, PPAR-γ agnostic, cytotoxicity, the reported compound mucronatin A, which shared the same carbon skeleton, exhibited moderate AchE inhibitory activity [7,[11][12][13][14][15][16]. Hence, in our search for the biological activities of isolated compounds, the cytotoxicity, and AchE inhibitory A C C E P T E D M A N U S C R I P T…”