Chang B K
Department of Medicine, VA Medical Center, Augusta, Georgia 30910.
Pancreas. 1991 Nov;6(6):631-6. doi: 10.1097/00006676-199111000-00003.
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 microM 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.
钙通道阻滞剂维拉帕米先前已被证明可通过多柔比星细胞内蓄积、潴留或代谢变化以外的机制增强胰腺腺癌细胞系对多柔比星的化学敏感性。鉴于我们对多胺生物合成和代谢感兴趣，且已知钙参与培养细胞血清再喂养诱导鸟氨酸脱羧酶（ODC）的过程，我们研究了维拉帕米对两种仓鼠胰腺腺癌细胞系中血清刺激的ODC活性的影响。在平台期的高分化（WD）PaCa和低分化（PD）PaCa细胞中，在1、5和10微摩尔/升维拉帕米浓度下，可观察到对血清诱导ODC 4小时的剂量依赖性抑制。在较高维拉帕米浓度下，ODC诱导的抑制作用与5毫摩尔/升α-二氟甲基鸟氨酸（DFMO，一种ODC的特异性酶抑制剂）所达到的抑制作用相当，且大于2毫摩尔/升乙二醇双四乙酸（EGTA）加缺钙血清所产生的抑制作用。作为对照纳入的对数期PD PaCa细胞，血清诱导的ODC较少，对维拉帕米、DFMO和缺钙血清再喂养反应的抑制程度也较小。在测量活性时加入维拉帕米，未发现对ODC酶有直接抑制作用。根据我们目前的数据，细胞内钙库对维拉帕米影响ODC活性的可能作用尚不清楚。然而，目前的研究结果表明，维拉帕米对细胞毒性的影响可能（至少部分）是通过抑制血清介导的ODC诱导来介导的。
