NOVEL MARINE ALKALOIDS FROM THE TUNICATE EUDISTOMA SP ARE POTENT REGULATORS OF CELLULAR GROWTH AND DIFFERENTIATION AND AFFECT CAMP-MEDIATEDPROCESSES

Six novel alkaloids that contain a fused tetracyclic pyrido[2,3,4-kl]a cridine ring system were purified recently from the Red Sea purple tun icate Eudistoma sp. Evaluation of the effects of these alkaloids on cu ltured neuroblastoma and fibroblast cells revealed that they possess p otent growth regulatory properties, and affect cell shape and adhesion . In mouse neuroblastoma cells, the Eudistoma alkaloids inhibited cell proliferation and induced a process of differentiation during which t he cells flattened onto the surface, increased considerably in size, a nd extended long neurites. In hamster fibroblasts the alkaloids slowed down cell multiplication, and caused an exceptional cell flattening o r elongation. In a virus-transformed derivative of the hamster fibrobl asts the alkaloids restored many aspects of normal cell growth and mor phology. In addition, several of the alkaloids mimicked the effects of cAMP analogs on two well-characterized cAMP-mediated processes involv ed in hepatic glucose metabolism-inhibition of pyruvate kinase (PK) ac tivity and induction of mRNA for phosphoenolpyruvate carboxykinase (PE PCK). All these effects suggest that the Eudistoma alkaloids may act o n the cAMP signaling system. However, a single application of these co mpounds was sufficient to completely block cell multiplication and to induce and sustain differentiation and ''reverse transformation''. Fur thermore, these effects were not readily reversible following removal of the drugs. In contrast, a single application of agents that mimic o r elevate cAMP induced a transient response that waned with time in cu lture, and the effects induced by constant elevation of cAMP reverse r apidly following drug removal. We propose that the Eudistoma alkaloids cause growth inhibition, differentiation, and reverse transformation by modifying the activity state of proteins that are involved in the r egulation of cell shape and adhesion and serve as a target for the cAM P and/or other second messenger systems. (C) 1993 Wiley-Liss, Inc.