dihydropyridines and Adrenocortical-Carcinoma

Steroid biosynthesis is initiated with transportation of cholesterol along with steroidogenic acute regulatory protein (StAR) into the mitchondria and is achieved with several steroidogenic enzymes. It has been reported that Ca(2+) channel blockers (CCBs), such as azelnidipine, efonidipine and nifedipine, suppress the biosynthesis of aldosterone and cortisol, but the overall effects of CCBs on steroid biosynthesis remain to be clarified. The present study was designed to evaluate the effects of CCBs on the expression of steroidogenic enzymes and the production of adrenal androgen, dehydroepiandrosterone sulfate (DHEA-S) that has anti-atherosclerotic actions. NCI-H295R human adrenocortical carcinoma cells and HepG2 human hepatoma cells were cultured for 24 hours with or without a CCB (amlodipine, efonidipine, nifedipine, azelnidipine R(-)-efonidipine, verapamil or diltiazem). HepG2 hepatoma cells were used to confirm the effects of CCBs on the expression of StAR. In fact, efonidipine and nifedipine increased the expression of StAR in HepG2 cells. Efonidipine and nifedipine, but not other examined CCBs, also increased the N(6), 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP)-induced StAR mRNA, which reflects the action of adrenocorticotropic hormone, and efonidipine and R(-)-efonidipine enhanced the dbcAMP-induced DHEA-S production in NCI-H295R adrenocortical carcinoma cells. Therefore, efonidipine and nifedipine might increase the expression of StAR and, in turn, efonidipine enhanced the dbcAMP-induced DHEA-S production, independent of Ca(2+) channel blockade. These results indicate that such effects are not associated with Ca(2+) influx. Moreover, only efonidipine enhanced the angiotensin II-induced expression of StAR mRNA (P < 0.01 vs. angiotensin II alone). In conclusion, efonidipine might exert an additional action beyond anti-hypertensive actions.

Topics: Adrenocortical Carcinoma; Angiotensin II; Bucladesine; Calcium Channel Blockers; Cell Line, Tumor; Dehydroepiandrosterone Sulfate; Dihydropyridines; Diltiazem; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Hydrocortisone; Nitrophenols; Organophosphorus Compounds; Phosphoproteins; RNA, Messenger; Verapamil

Blockade of a mineralocorticoid receptor is a clinically useful approach to the prevention of cardiovascular disease. The present study was designed to evaluate the effect of azelnidipine, a unique dihydropyridine Ca(2+) channel blocker, on aldosterone production in the human adrenocortical cell line NCI-H295R. Azelnidipine inhibited angiotensin II- and KCl-induced expression of steroid 11beta-hydroxylase, steroid 18-hydroxylase, and the alpha1H subunit of the T-type Ca(2+) channel, and suppressed steroid biosynthesis in H295R cells by the same amount as efonidipine. On the basis of these findings, azelnidipine appears to suppress steroid biosynthesis in H295R cells beyond the blockade of L-type calcium channels.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Aldosterone; Angiotensin II; Azetidinecarboxylic Acid; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cell Line, Tumor; Cytochrome P-450 CYP11B2; Dihydropyridines; Gene Expression Regulation; Humans; Nitrophenols; Organophosphorus Compounds; Potassium Chloride; Steroid 11-beta-Hydroxylase