ABSTRACT
Although radiation therapy is an effective treatment modality in many cancers, there is an urgent need to develop therapeutic drugs capable of overcoming radioresistance or minimizing normal tissue toxicity. A wide variety of marine-derived bioactive compounds have been screened for anti-cancer drug discovery, but little is known regarding radiation therapy applications. In this study, six different extracts of marine sponges collected from the Micronesian sea were screened for anti-cancer and radiosensitizing activity. Two extracts derived from Agelas sponges collected off the coast of Kosrae and Chuuk, the Federated States of Micronesia significantly decreased clonogenic survival of hepatocellular carcinoma (HCC) cells after exposure to ionizing radiation (IR). The Agelas extracts augmented IR-induced apoptosis and accumulation of reactive oxygen species (ROS). Endoplasmic reticulum (ER) stress was increased via unfolded protein response stimulation, which induced autophagy. N-acetylcysteine, a ROS scavenger, diminished ER stress and autophagy induction effects. This result indicated that Agelas extracts may sensitize HCC cells to IR via ROS overproduction in vitro. Our findings suggest that the Agelas sp. may have potential utility in radiosensitizer development.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor/drug effects , Radiation-Sensitizing Agents/pharmacology , Acetylcysteine/metabolism , Agelas/metabolism , Animals , Apoptosis/drug effects , Autophagy/drug effects , Carcinoma, Hepatocellular/pathology , Cell Extracts/pharmacology , Endoplasmic Reticulum Stress/drug effects , Humans , Liver Neoplasms/drug therapy , Micronesia , Porifera/metabolism , Reactive Oxygen Species/metabolismABSTRACT
The marine sponge genus Agelas comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the first time summarized secondary metabolites from Agelas sponges discovered in the past 47 years together with their bioactive effects.
Subject(s)
Agelas/metabolism , Biological Products/metabolism , Agelas/chemistry , Animals , Aquatic Organisms , Biological Products/chemistryABSTRACT
Agelasine G (1), a known bromine-containing diterpene alkaloid, was isolated as a new type of protein tyrosine phosphatase (PTP) 1B inhibitor together with ageline B (2), an inactive debromo-derivative of 1, from the marine sponge Agelas nakamurai collected at Iriomote Island in Okinawa, Japan. Further biological evaluations revealed that compound 1 exhibited selective inhibitory activity against PTP1B over T-cell PTP and CD45 phosphatase. Compound 1 also enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells more strongly than compound 2. The results obtained in this study suggest that compound 1 activates the insulin signaling pathway by inhibiting PTP1B activity.
Subject(s)
Agelas/chemistry , Alkaloids/chemistry , Diterpenes/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Agelas/metabolism , Alkaloids/isolation & purification , Alkaloids/toxicity , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Diterpenes/isolation & purification , Diterpenes/toxicity , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/toxicity , Humans , Insulin/metabolism , Japan , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Phosphorylation/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pyrroles/chemistry , Signal Transduction/drug effectsABSTRACT
Game-SET-match: Pyrrole aminoimidazole alkaloids (PAIs) are metabiosynthesized from chlorinated analogues of oroidin by cell-free enzyme preparations from PAI-producing sponges. Evidence and implications for the biosynthesis of PAIs include putative single-electron transfers (SETs) that promote C-C bond-forming reactions of precursors.
Subject(s)
Agelas/metabolism , Alkaloids/biosynthesis , Imidazoles/metabolism , Porifera/metabolism , Pyrroles/metabolism , Agelas/chemistry , Alkaloids/chemical synthesis , Animals , Imidazoles/chemical synthesis , Porifera/chemistry , Pyrroles/chemical synthesisABSTRACT
Chemical investigation of Indonesian marine sponges Agelas linnaei and A. nakamurai afforded 24 alkaloid derivatives representing either bromopyrrole or diterpene alkaloids. A. linnaei yielded 16 bromopyrrole alkaloids including 11 new natural products with the latter exhibiting unusual functionalities. The new compounds include the first iodinated tyramine-unit bearing pyrrole alkaloids, agelanesins A-D. These compounds exhibited cytotoxic activity against L5178Y mouse lymphoma cells with IC(50) values between 9.25 and 16.76 muM. Further new compounds include taurine acid substituted bromopyrrole alkaloids and a new dibromophakellin derivative. A. nakamurai yielded eight alkaloids among them are three new natural products. The latter include the diterpene alkaloids (-)-agelasine D and its oxime derivative and the new bromopyrrole alkaloid longamide C. (-)-Agelasine D and its oxime derivative exhibited cytotoxicity against L5178Y mouse lymphoma cells (IC(50) 4.03 and 12.5 microM, respectively). Furthermore, both agelasine derivatives inhibited settling of larvae of Balanus improvisus in an anti-fouling bioassay and proved to be toxic to the larvae. (-)-Agelasine D inhibited the growth of planktonic forms of biofilm forming bacteria S. epidermidis (MIC<0.0877 microM) but did not inhibit biofilm formation whereas the oxime derivative showed the opposite activity profile and inhibited only biofilm formation but not bacterial growth. The structures of the isolated secondary metabolites were elucidated based on extensive spectroscopic analysis involving one- and two-dimensional NMR as well as mass spectrometry and comparison with literature data.
