INHIBITORY EFFECTS OF A CALCIUM-ANTAGONIST ON ORNITHINE DECARBOXYLASE INDUCTION IN PANCREATIC-CANCER CELL-LINES

The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation, retention, or metabolism of doxorubicin. Because of our interest in polyamine biosynthesis and metabolism and the known involvement of calcium in the induction of ornithine decarboxylase (ODC) by serum refeeding of cultured cells, the effects of verapamil on the serum-stimulated ODC activity in two hamster pancreatic adenocarcinoma cell lines were examined. In plateau phase well-differentiated (WD) PaCa and poorly differentiated (PD) PaCa cells, a dose-dependent inhibition of the 4-h serum induction of ODC was seen at concentrations of 1, 5, and 10-mu-M verapamil. At the higher concentrations of verapamil, the inhibition of ODC induction was comparable to that achieved with 5 mM alpha-difluoromethylornithine (DFMO, a specific enzyme inhibitor of ODC) and greater than that seen with 2 mM EGTA plus calcium-depleted serum. Log phase PD PaCa cells, included for comparison, showed less ODC induction with serum and lesser degrees of inhibition of the response to serum refeeding with verapamil, DFMO, and calcium depletion. No direct inhibition of the ODC enzyme was found when verapamil was added at the time the activity was measured. Based on our present data, a possible influence of intracellular calcium pools in the verapamil effect on ODC activity is unclear. Nevertheless, the present findings suggest that verapamil's effects on cytotoxicity may be mediated (at least in part) by inhibition of the serum-mediated induction of ODC.