Ultrastructural and biochemical evidence of apoptosis induced by a novel inhibitor of protein geranylgeranylation in human MIA PaCa-2 pancreatic cancer cells

Analogs of geranylgeranyl diphosphate (GGdP) have been demonstrated to inhibit the geranylgeranylation of proteins, producing cytotoxic activity in human prostate cancer cells. A detailed study is reported on the programmed cell death in vitro of human exocrine pancreas cancer cells (MIA PaCa-2) induced by the most active compound of this series of geranylgeranylation inhibitors, the dipotassium salt of (E,E,E){2-oxo-2-[[(3,7,11,15- tetramethyl-2,6,10,14-hexadecatetraenyl)-oxy]amino]ethyl} phosphonic acid (BAL 9504), using transmission and scanning electron microscopy (SEM). The results show that, after 72 h of treatment with BAL 9504, 25 μM, most MIA PaCa-2 cells display the typical morphological features of apoptosis, including condensation of nuclear chromatin, dilation of endoplasmic reticulum, and fragmentation of both nucleus and cytoplasm, giving rise to small membrane-bound vesicles (apoptotic bodies); surface protrusions and blebs are well demonstrated by SEM. The electrophoresis showed the presence of various bands corresponding to fragmented DNA of 180 base pairs, or multiples of this length, thus indicating that BAL 9504 effectively induces apoptosis. The present study provides the first evidence that inhibition of protein geranylgeranylation produces apoptosis in human MIA PaCa-2 exocrine pancreas cancer cells.