jasplakinolide and Lymphoma

Two new jaspamide derivatives 2 and 3, together with the parent compound jaspamide (1) have been isolated from the marine sponge Jaspis splendens collected in Kalimantan (Indonesia). The structures of the new compounds were unambiguously elucidated based on 1D and 2D NMR spectral data, mass spectrometry and comparison with jaspamide (1). The new derivatives inhibited the growth of mouse lymphoma (L5178Y) cell line in vitro with IC(50) values of <0.1 microg/mL.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Depsipeptides; Drug Screening Assays, Antitumor; Indonesia; Inhibitory Concentration 50; Lymphoma; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Porifera

The retro-retinoids, metabolites of vitamin A (retinol), belong to a family of lipophilic signalling molecules implicated in regulation of cell growth and survival. Growth-promoting properties have been ascribed to 14-hydroxy-retro-retinol (14HRR), while anhydroretinol (AR) was discovered to act as a natural antagonist triggering growth arrest and death by apoptosis. Based on morphological studies and inhibition of apoptosis by the kinase blocker, herbimycin A, it has been suggested that retro-retinoids exhibit their function in the cytosolic compartment. F-actin emerged as a functional target for retro-retinoid action. By FACS analysis and fluorescence microscopy of phalloidin-FITC labeled cells we demonstrated that F-actin reorganization was an early event in AR-triggered apoptosis. Fluorescence images of AR-treated fibroblasts displayed short, thick, stick-like and punctate structures, and membrane ruffles at the cell periphery along with an increased diffuse staining pattern. Reversal of the AR effect by 14HRR or retinol indicates that F-actin is a common site for regulation by retro-retinoids. Inhibition of both cell death and actin depolymerisation by bcl-2 implies that cytoskeleton reorganization is downstream of bcl-2-related processes. Furthermore, stabilization of microfilaments by jasplakinolide increased the survival potential of AR treated cells, while weakening the cytoskeleton by cytochalasin B abetted apoptosis. Thus the cytoskeleton is an important way station in a communication network that decides whether a cell should live or die.

Topics: 3T3 Cells; Actins; Animals; Antineoplastic Agents; Apoptosis; Benzoquinones; Cell Survival; Cytochalasin B; Cytosol; Depsipeptides; Diterpenes; DNA Damage; Fibroblasts; Flow Cytometry; Kinetics; Lactams, Macrocyclic; Lymphoma; Mice; Peptides, Cyclic; Quinones; Retinoids; Rifabutin; Tumor Cells, Cultured; Vitamin A