Apoptosis induction and cell cycle perturbation in established cell lines by peroxysomicine A(1) (T-514)

Peroxysomicine A(1), a novel potential anticancer compound induced cell dea th in established cell lines and in a primary culture of rat neonatal cardi omyocytes. Non-transformed cells are less sensitive to the compound than tr ansformed cell lines. Fluorescent microscopy of dying cells stained with DN A-specific dyes revealed chromatin condensation and nuclear fragmentation a s well as membrane blebbing characteristic of apoptosis. Flow cytometry of cells treated with peroxysomicine A(1), demonstrated appearance of cells co ntaining less than 2C DNA, that indicated degradation of nuclear DNA, anoth er hallmark of apoptotic cell death. Z-VAD, a nonspecific caspase inhibitor , prevented DNA fragmentation but not cell death registered by permeabiliza tion of cell outer membrane. Peroxysomicine A(1) also inhibited proliferati on of various cell lines. Flow cytometry analysis showed significant accumu lation of dividing cells in G(2)/M phases of cell cycle indicating, most li kely delay in G(2) These results provide initial insight into the mechanism s of action of peroxysomicine A(1) and suggest that peroxysomicine A(1) is a potent inhibitor of cell proliferation and inducer of apoptosis and may b e a useful antineoplastic chemotherapeutic agent.