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

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 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.

• Authors: Shu-Fen Liou, Hung-Hong Lin, Jyh-Chong Liang, Ing-Jun Chen, Jwu-Lai Yeh
• Journal: Toxicology (Toxicology) Vol. 256 Issue 1-2 Pg. 13-24 (Feb 04 2009) ISSN: 0300-483X [Print] Ireland
• PMID: 19056458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Antagonists
• Adrenergic alpha-Antagonists
• Anisoles
• Benzimidazoles
• Dihydropyridines
• Fluorescent Dyes
• Receptors, Adrenergic, alpha-1
• labedipinedilol A
• Oncogene Protein v-akt
• Mitogen-Activated Protein Kinases
• Caspase 3
• Caspase 9
• bisbenzimide ethoxide trihydrochloride

Topics

• Adrenergic alpha-1 Receptor Antagonists
• Adrenergic alpha-Antagonists (pharmacology)
• Anisoles (pharmacology)
• Apoptosis (drug effects)
• Benzimidazoles
• Blotting, Western
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dihydropyridines (pharmacology)
• Fluorescent Dyes
• Humans
• Male
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (metabolism)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Oncogene Protein v-akt (genetics, metabolism)
• Prostatic Neoplasms (pathology)
• Receptors, Adrenergic, alpha-1 (metabolism)
• Signal Transduction (drug effects)