Growth-inhibitory activity of melatonin on human androgen-independent DU 145 prostate cancer cells

Abstract

BACKGROUND. The pineal hormone melatonin has been shown to exert a direct oncostatic activity on neoplastic cells, particularly from breast cancer. In the present study, we evaluated the effects of melatonin on the proliferation and on the cell cycle distribution of human androgen-independent DU 145 prostate cancer cells. Experiments were also performed to gain insights into the possible mechanism of action of the hormone. METHODS. The effects of melatonin on DU 145 cell proliferation was analyzed by counting the cells by hemocytometer at the end of treatment. The effects of the pineal hormone on cell cycle distribution were evaluated by FACS analysis. RT-PCR studies were performed to detect Mel 1a and Mel 1b expression in DU 145 cells. The cellular localization of 125 I-melatonin binding sites was investigated by radioreceptor assay. A commercially available binding-protein assay kit was utilized to evaluate intracellular cAMP levels. RESULTS. Melatonin, in physiological doses, significantly inhibited DU 145 cell proliferation and induced cell cycle withdrawal by accumulating cells in G0/G1 phase. The mRNA for Mel 1a receptors was found to be expressed in DU 145 cells; however, by radioreceptor assay, no binding sites for 125 I-melatonin could be detected in membrane preparations, suggesting that, in these cells, the level of translation of this mRNA is too low to possibly mediate the antiproliferative action of the hormone. In agreement with this hypothesis, melatonin did not affect forskolin-induced intracellular cAMP accumulation. Binding sites for 125 I-melatonin were found in nuclear extracts of DU 145 cells. CONCLUSIONS. Melatonin exerts a direct oncostatic activity on human androgenindependent prostate cancer cells, by affecting cell cycle progression. This activity seems to be mediated by nuclear, but not by membrane, receptors.

Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be prevented by melatonin

“…Although some (Irani et al, 1997;Joneson and Bar-Sagi, 1998) have claimed that other antioxidants, such as N-acetyl-lcysteine (NAC) and superoxide dismutase (SOD), can inhibit the mitogenic activity in ras-transformed cells, this is first report that melatonin can block ras-induced cell growth, which provides a new insight for its oncostatic ability. Accumulated reports (Panzer et al, 1998;Cos and Sanchez-Barcelo, 2000;Marelli et al, 2000) showing that melatonin exerts oncostatic action that make it a potential supplement in the treatment of various cancers in vitro, in vivo, and in clinical therapy further support our hypothesis. Melatonin inhibits MCF-7 human breast cancer cell proliferation by inducing a G0/G1 arrest, which is dependent on an increased expression of p21WAF1 protein (Mediavilla et al, 1999).…”

Basic Mechanisms Involved in the Anti-Cancer Effects of Melatonin

“…-Through the activation of MT1 receptor -By attenuating sex steroid-induced calcium influx [9] LNCaP human prostate cancer cells -Melatonin (1 nM) inhibited cell proliferation, and influenced cell cycle distribution by inducing an accumulation of the cells in G0/G1 and a decrease in S phase [10] Androgen-independent DU 145 prostate cancer cells -Melatonin (1 nM) inhibited cell proliferation and induced cell cycle withdrawal by accumulating cells in G0/G1 phase. These effects seem to have been mediated by nuclear, but not by membrane, receptors [11] Xenograft of androgen sensitive (LNCaP) and androgeninsensitive (PC-3) human prostate cancer cells, in nude mice -Melatonin (4 μg/g BW) inhibited the growth of LNCaP tumors, without affecting the growth of PC-3 xenografts -MT1 membrane melatonin receptors are expressed in LNCaP cells, but not in PC-3 cells [12] LNCaP human prostate cancer cells -Melatonin (3 mM, for 48 h) induced apoptosis via mitogen-activated protein kinases (MAPKs) [13] MG-63 osteosarcoma cells -Melatonin(10 μM to 0.1 pM) had no effects on cell proliferation [14] SK-N-MC cells, a human Ewing sarcoma cell line -Melatonin (50 μM-1 mM) synergized with vincristine (5-10 nM) or ifosfamide (100 μM-1 mM) potentiating apoptosis…”

Melatonin as a Biomarker of Circadian Dysregulation

“…30). Several in vitro studies have reported a reduction in the growth of malignant cells and/or tumors of the breast (31)(32)(33)(34)(35) prostate (36)(37)(38)(39)(40)(41), and other tumor sites (42)(43)(44)(45)(46) by both pharmacologic and physiologic doses of melatonin. In rodent models, pinealectomy has been found to enhance tumor growth (47), and exogenous melatonin administration has shown anti-initiating (48) and oncostatic (49)(50)(51)(52) activities in various chemically induced cancers as well as in virus-transmitted tumors in mice (53).…”