Natural sources of potential anti-tumorigenic and anti-metastatic agents are, for example, provided by diverse marine sponges. A prominent agent is the bioactive (+)-Aeroplysinin-1 isolated from the marine demosponge Aplysina aerophoba.
Over 10% of pheochromocytoma and paraganglioma (PPGL) patients have the malignant disease at their first presentation in the clinic. Development of malignancy and the underlying molecular pathways in PPGLs are poorly understood, and effective treatment strategies are missing.
Marine sponges provide a natural source of promising anti-tumorigenic and anti-metastatic agents. The researchers evaluated the anti-tumorigenic and anti-metastatic potential of Aeroplysinin-1 and Isofistularin-3, two secondary metabolites isolated from the marine spongeAplysina aerophoba, on pheochromocytoma cells.
Aeroplysinin-1 diminished the number of proliferating cells and reduced spheroid growth significantly. Beside this anti-tumorigenic activity, Aeroplysinin-1 decreased the migration ability of the cells significantly (p = 0.01), whereas, the invasion capacity was not affected.
Aeroplysinin-1 diminished the high adhesion capacity of the MTT cells to collagen (p < 0.001) and, furthermore, reduced the ability to form spheroids significantly. Western Blot and qRT-PCR analysis showed a downregulation of integrin β1 that might explain the lower adhesion and migration capacity after Aeroplysinin-1 treatment. Isofistularin-3 showed only a negligible influence on proliferative and pro-metastatic cell properties.
These in vitro investigations show promise for the application of the sponge-derived marine drug, Aeroplysinin-1 as anti-tumorigenic and anti-metastatic agent against PPGLs for the first time.
Anti-Proliferative Activity of Aeroplysinin-1 and Isofistularin-3 in Vitro
Aeroplysinin-1 induced apoptosis, analyzed by caspase (casp)-3 and casp-7 activity assay, in a concentration-dependent manner but predominant at a lower concentration. Furthermore, gene expression analysis demonstrated a reduction of casp-3 and casp-7 after treatment with 10 µM Aeroplysinin-1 in the MTT cells.
Isofistularin-3 reduced caspase activity at higher concentrations (50 µM), whereas, expression of the caspase genes was induced after 48 h treatment with a concentration of 10 µM.
The necrosis-associated genes were up-regulated after 48 h treatment with Isofistularin-3. Furthermore, Becn1 as a marker of autophagy was increased after Isofistularin-3 treatment
Influence of Aeroplysinin-1 and Isofistularin-3 on Cells’ Pro-Metastatic Behavior
Isofistularin-3 did not influence MTT cell migration and invasion. Furthermore, the adhesion to the extracellular matrix proteins collagen and fibronectin was analyzed. Aeroplysinin-1 significantly diminished the high adhesion capacity of the MTT cells to collagen. The adhesion capacity of the pheochromocytoma cell was not affected by Isofistularin-3
In vitro investigations show promise for the application of Aeroplysinin-1 as anti-tumorigenic and anti-metastatic agent against pheochromocytoma and paraganglioma (PPGLs). The mechanism is based on the reduction of the integrin β1 expression.
The application of Aeroplysinin-1 and other sponge-derived secondary metabolites provides a promising therapeutic strategy especially for the treatment of metastatic PPGLs and other tumor entities with the tendency for metastatic spread.