INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME MODULATE MITOSIS AND GENE-EXPRESSION IN PANCREATIC-CANCER CELLS

The angiotensin-converting enzyme (ACE) inhibitor captopril inhibits m itosis in several cell types that contain ACE and renin activity. In t he present study, we evaluated the effect of the ACE inhibitors captop ril and CGS 13945 (10(-8) to 10(-2) M) on proliferation and gene expre ssion in hamster pancreatic duct carcinoma cells in culture. These cel ls lack renin and ACE activity. Both ACE inhibitors produced a dose-de pendent reduction in tumor cell proliferation within 24 hr. Captopril at a concentration of 0.36 mM and CGS 13945 at 150 mu M decreased cell ular growth rate to approximately half that of the control. Neither dr ug influenced the viability or the cell cycle distribution of the tumo r cells. Slot blot analysis of mRNA for four genes, proliferation asso ciated cell nuclear antigen (PCNA), K-ras, protein kinase C-beta (PKC- beta) and carbonic anhydrase II (CA II) was performed. Both ACE inhibi tors increased K-ras expression by a factor of 2, and had no effect on CA II mRNA levels. Captopril also lowered PCNA by 40% and CGS 13945 l owered PKC-beta gene expression to 30% of the control level. The data demonstrate that ACE inhibitors exhibit antimitotic activity and diffe rential gene modulation in hamster pancreatic duct carcinoma cells. Th e absence of renin and ACE activity in these cells suggests that the a ntimitotic action of captopril and CGS 13945 is independent of renin-a ngiotensin regulation. The growth inhibition may occur through downreg ulation of growth-related gene expression.