Inhibition of human prostate cancer cells proliferation by a selective alpha1-adrenoceptor antagonist labedipinedilol-A involves cell cycle arrest and apoptosis

• Published in: Toxicology (Amsterdam) Vol. 256; no. 1; pp. 13 - 24
• Main Authors: Liou, Shu-Fen, Lin, Hung-Hong, Liang, Jyh-Chong, Chen, Ing-Jun, Yeh, Jwu-Lai
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ireland Ltd 04.02.2009; Elsevier
• Subjects: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists - pharmacology; Anisoles - pharmacology; Anti-proliferation; Apoptosis; Apoptosis - drug effects; Benzimidazoles; Biological and medical sciences; Blotting, Western; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dihydropyridines - pharmacology; Emergency; Fluorescent Dyes; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Membrane Potentials - drug effects; Mitochondrial Membranes - metabolism; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Nephrology. Urinary tract diseases; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - metabolism; Prostate cancer; Prostatic Neoplasms - pathology; Receptors, Adrenergic, alpha-1 - metabolism; Signal Transduction - drug effects; Toxicology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; α 1-Adrenoceptor antagonist; α 1-Adrenoceptor antagonist; Anti-proliferation; Prostate cancer; Cell cycle; Apoptosis; Human; Cell proliferation; α1-Adrenoceptor antagonist; Urinary system disease; Prostate disease; α1-Adrenergic receptor; Malignant tumor; Cell death; Inhibitor; Antagonist; Inhibition; Adrenergic receptor; Male genital diseases; Tumor cell; Cancer
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2008.10.025

Abstract 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 α1 -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 α1 -adrenoceptors in this cellular response is suggested. Labedipinedilol-A-induced growth inhibition was associated with G0 /G1 arrest, and G2 /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 α1 -adrenoceptor blockade, and the apoptotic effects of labedipinedilol-A primarily through caspases and MAPKs mediated pathways.