dihydropyridines and Prostatic-Neoplasms

For decades, conflicting results were published regarding the increased risk of Prostate cancer (PCa) among calcium channel blocker (CCB) users.. We aimed to evaluate the association between PCa and CCB exposure and assess moderating factors.. We performed a systematic literature search in PubMed, Embase, and Cochrane databases for observational and randomized studies published until November 2020 with no language limitations, including data on the risk for PCa in CCB users compared with non-CCB users. We applied a random-effects model meta-analysis to pool results. In addition, we investigated potential moderating factors, such as CCB type, study type, participants' age, and duration of exposure, using meta-regression methods.. In our primary analysis, we included 18 studies. A statistically significant 5% increase in the risk for PCa was observed among CCB users (risk ratio [RR] = 1.05; 95% confidence interval [CI]: 1.01-1.10), with no significant association between the duration of exposure to CCBs and the risk for PCa (RR = 1.08; 95% CI: 0.98-1.19 for exposure for < 5years and RR = 1.01; 95% CI: 0.9-1.14 for exposure ≥ 5 years). The association remained statistically significant for the subgroup of dihydropyridines (RR = 1.13; 95% CI: 1.05-1.22). In addition, the association was not influenced by participants' age.. CCBs are an important modality in treating hypertension. The 5% increased risk observed in the current meta-analysis could be influenced by residual confounding factors and should not affect hypertension treatment guidelines until more studies provide additional clinical information.

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Hypertension; Male; Odds Ratio; Prostatic Neoplasms

Topics: Aged; Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; B7-H1 Antigen; Biphenyl Compounds; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin B1; Dihydropyridines; DNA-Binding Proteins; Drug Resistance, Neoplasm; E2F1 Transcription Factor; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; PC-3 Cells; Polo-Like Kinase 1; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; RNA, Small Interfering; Survivin; Tumor Escape

In this research, we conducted an in vitro analysis to evaluate the prostate cancer cells response to labedipinedilol-A in order to determine the effect of this selective alpha(1)-adrenoceptor antagonist to suppress prostate cancer cell growth by affecting cell proliferation and apoptosis. Here, we report that treatment of androgen-sensitive (LNCaP) and androgen-insensitive (PC-3) prostate cancer cells with labedipinedilol-A inhibited cell proliferation in concentration-dependent and time-dependent manners. Moreover, norepinephrine-stimulated proliferation of both cell lines are markedly inhibited by labedipinedilol-A. The probable involvement of alpha(1)-adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G(0)/G(1) arrest, and G(2)/M arrest depending upon concentrations. Cell cycle blockade was associated with reduced amounts of cyclin D1/2, cyclin E, Cdk2, Cdk4, and Cdk6 and increased levels of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27). In addition, labedipinedilol-A also induced apoptosis in PC-3 cells, as determined by using Hoechst 33342 staining, DNA fragmentation, and Annexin V staining assay. Furthermore, labedipinedilol-A triggered the mitochondrial apoptotic pathway, as indicated by increasing the expression of Bax, but decreasing the level of Bcl-2, resulting in mitochondrial membrane potential loss, cytochrome c release, and activation of caspase-9 and -3. We further investigated the role of MAPK cascades in the anti-proliferative and apoptosis effects of labedipinedilol-A, and confirmed that labedipinedilol-A could activate JNK1/2 but not p38 in both cell lines. Unlike JNK1/2, however, labedipinedilol-A treatment resulted in down-regulation of phospho-ERK1/2 expression. We concluded that labedipinedilol-A possessed the growth-suppressive and apoptotic effects on LNCaP and PC-3 cells by its alpha(1)-adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and MAPKs mediated pathways.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Anisoles; Apoptosis; Benzimidazoles; Blotting, Western; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dihydropyridines; Fluorescent Dyes; Humans; Male; Membrane Potentials; Mitochondrial Membranes; Mitogen-Activated Protein Kinases; Oncogene Protein v-akt; Prostatic Neoplasms; Receptors, Adrenergic, alpha-1; Signal Transduction

In human prostate cancer PC3 cells, the effect of Y-24180, a presumed specific platelet activation factor (PAF) receptor antagonist, on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2 as a Ca2+-sensitive fluorescent probe. Y-24180 (1-10 microM) caused a rapid and sustained [Ca2+]i rise in a concentration-dependent manner. The [Ca2+]i rise was prevented by 40% by removal of extracellular Ca2+, but was not changed by dihydropyridines, verapamil and diltiazem. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of 10 microM Y-24180 on [Ca2+]i was reduced by 67%; conversely, depletion of Ca2+ stores with 10 microM Y-24180 abolished thapsigargin-induced [Ca2+]i rise. U73122, an inhibitor of phospholipase C, inhibited ATP-, but not Y-24180-induced [Ca2+]i rise. Activation of protein kinase C with phorbol-12-myristate-13-acetate (PMA) enhanced Y-24180-induced [Ca2+]i rise by 70%. Overnight treatment with 0.1-10 microM Y-24180 inhibited cell proliferation in a concentration-dependent manner. Collectively, these results suggest that Y-24180 acts as a potent and cytotoxic Ca2+ mobilizer in prostate cancer cells, by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release. Since alterations in Ca2+ movement may interfere with many cellular signalling processes unrelated to modulation of PAF receptors, caution must be applied in using this reagent as a selective PAF receptor antagonist.

Topics: Adenosine Triphosphate; Azepines; Calcium; Calcium Signaling; Cell Proliferation; Dihydropyridines; Diltiazem; Enzyme Inhibitors; Fura-2; Humans; Male; Phorbol Esters; Platelet Membrane Glycoproteins; Prostatic Neoplasms; Protein Kinase C; Receptors, G-Protein-Coupled; Signal Transduction; Thapsigargin; Triazoles; Tumor Cells, Cultured; Verapamil

We have isolated etoposide-resistant prostatic cancer cell lines, P/VP10 and P/VP20, to investigate the multidrug resistance (MDR) mechanism and to find MDR reversal agents.. We examined expression of MDR-related genes and screened reversal agents of MDR in P/VP20 cells.. These cells demonstrated a non-P-glycoprotein (P-gp)-mediated MDR phenotype with overexpression of MDR-associated protein (MRP) mRNA due to MRP DNA amplification. A 1,4-dihydropyridine derivative, bis(4-pyridylmethyl)4-[2-(3-methyl-5,6- dihydro-1,4-dithiinyl)]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar boxylate (NIK250), was found to overcome MDR in P/VP20 cells.. NIK250 might be useful in reversing MDR, which often develops during chemotherapy of advanced or hormone-resistant prostatic cancer.

Topics: Cell Line; Dihydropyridines; Drug Resistance, Multiple; Etoposide; Humans; Male; Prostatic Neoplasms; RNA, Messenger; Sulfur Compounds; Tumor Cells, Cultured; Tumor Stem Cell Assay