title: Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in androgen-responsive prostate cancer cell LNCaP.
abstract: Sirtinol is a purported specific inhibitor of the nicotinamide adenine dinucleotide (NAD)-dependent type III histone deacetylase (also known as sirtuin). Sirtinol has been used extensively to identify chemopreventive/chemotherapeutic agents that modulate the sirtuins. However, the molecular effect of sirtinol other than serving as sirtuin inhibitor in cells is less clear. The present study addressed this deficiency in the literature. Based on structural similarity with plant-derived cancer preventive/therapeutic compounds such as 3', 3'-diindolylmethane, resveratrol, and genistein, we hypothesized that sirtinol may act on pathways similar to that affected by these compounds in the human prostate cancer cell LNCaP. We found that treatment of LNCaP cells with sirtinol led to concentration-dependent effects on multiple pathways. Sirtinol inhibited LNCaP cell cycle and growth that was correlated with up-regulation of cyclin-dependent kinase inhibitor 1A mRNA and protein levels. This effect of sirtinol may due in part to modulation of androgen, estrogen, and insulin-like growth factor-1 mediated pathways as sirtinol treatment led to inhibition of mRNA and protein expression of marker genes involved in these pathways. We also found sirtinol activates aryl hydrocarbon-dependent pathways in LNCaP cells. The effects of sirtinol were observed at 25 µM, a concentration lower than Ki (38 µM) for sirtuin activity. Based on these results we reasoned that sirtinol exerts pleiotropic effects in cells and that biological effects of sirtinol may not be due solely to inhibition of sirtuin.
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705, USA.
authors.forename: Thomas T Y
authors.initials: TT
authors.lastname: Wang
authors.forename: Norberta W
authors.initials: NW
authors.lastname: Schoene
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000728:Androgens / Q000235:genetics / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology*; D008517:Phytotherapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000728:Androgens; D016588:Anticarcinogenic Agents; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004967:Estrogens; D009284:Naphthols; D018160:Receptors, Cytoplasmic and Nuclear; C439060:sirtinol; D007334:Insulin-Like Growth Factor I; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D037761:Sirtuins