Combination of melatonin and tamoxifen as a chemoprophylaxis against N-nitroso-N-methylurea-induced rat mammary tumors

Kothari, Ami; Borges, Anita; Ingle, Arvind; Kothari, Lalita S.

doi:10.1016/s0304-3835(96)04493-x

Cited by 21 publications

(5 citation statements)

References 21 publications

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“…Melatonin, a hormone produced by the pineal gland, demonstrates a circadian rhythm (low during the day and elevated at night). Several reports have been published regarding the relationship between melatonin levels and mammary carcinogenesis, [28][29][30] colon carcinogenesis, 31) cell proliferation, 32) and DNA synthesis in cultured cells. 33) Since EMF has been reported to depress melatonin production, 34,35) this parameter was also assessed in the present study.…”

Section: Discussionmentioning

confidence: 99%

The 1.5 GHz Electromagnetic Near‐field Used for Cellular Phones Does Not Promote Rat Liver Carcinogenesis in a Medium‐term Liver Bioassay

Imaida

Taki

Watanabe³

et al. 1998

Japanese Journal of Cancer Research

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We have recently established that local exposure to a 929.2 MHz electromagnetic near-field, used for cellular phones, does not promote rat liver carcinogenesis in a medium-term bioassay system. In the present study, a 1.439 GHz electromagnetic near-field (EMF), another microwave band employed for cellular phones in Japan, was similarly investigated. Time division multiple access (TDMA) signals for the Personal Digital Cellular (PDC) Japanese cellular telephone standard system were directed to rats through a quarter-wavelength monopole antenna. Numerical dosimetry showed that the peak SARs within the liver were 1.91-0.937 W/kg, while the whole-body average specific absorption rates (SARs) were 0.680-0.453 W/kg, when the time-averaged antenna radiation power was 0.33 W. Exposure was for 90 min a day, 5 days a week, over 6 weeks, to male F344 rats given a single dose of diethylnitrosamine (200 mg/kg, i.p.) 2 weeks previously. At week 3, all rats were subjected to a two-thirds partial hepatectomy. At week 8, the experiment was terminated and the animals were killed. Carcinogenic potential was scored by comparing the numbers and areas of the induced glutathione S-transferase placental form (GST-P)-positive foci in the livers of exposed (48) and sham-exposed rats (48). Despite increased serum levels of corticosterone, adrenocorticotropic hormone (ACTH) and melatonin, the numbers and the areas of GST-Ppositive foci were not significantly altered by the exposure. These findings clearly indicated that local body exposure to a 1.439 GHz EMF, as in the case of a 929.2 MHz field, has no promoting effect on rat liver carcinogenesis in the present model.

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Section: Discussionmentioning

confidence: 99%

The 1.5 GHz Electromagnetic Near‐field Used for Cellular Phones Does Not Promote Rat Liver Carcinogenesis in a Medium‐term Liver Bioassay

Imaida

Taki

Watanabe³

et al. 1998

Japanese Journal of Cancer Research

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“…MCF‐7 cells express high levels of estrogen receptor (ER), and are stimulated to grow by estradiol. Melatonin inhibits this mitogenic action [18, 19] and enhances the sensitivity of MCF‐7 to tamoxifen [18, 20, 21]. Moreover, it has been shown to suppress the expression of estrogen‐regulated genes and to downregulate ER expression itself, probably through transcriptional regulation [22].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin‐induced oncostatic effects

Cini¹,

Neri²,

Pacini

et al. 2005

Journal of Pineal Research

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Melatonin is endowed with a growth inhibitory effect in MCF-7 breast cancer cells whose mechanism has been related to an antiestrogenic activity exerted by inhibition of binding of the estradiol-estrogen receptor complex to its DNA responsive element. Looking for downstream gene determinants of this effect, we performed a transcriptome profiling by high-density microarrays of estrogen-treated MCF-7 cells exposed or not to melatonin. We found that cyclin D1 was one of the main downregulated genes by melatonin. Validation experiments clearly confirm that in MCF-7 cells the estrogen-induced growth inhibitory activity of melatonin is consistently associated with inhibition of estrogen-elicited cyclin D1 induction. This effect is almost purely transcriptional. Reporter gene assays indicate that the same portion of the cyclin D1 promoter which confers estrogen sensitivity, encompassing a potential cAMP responsive element binding site, is repressed by melatonin. Transcriptional downregulation of cyclin D1 is the key molecular event for melatonin's antiproliferative activity, as this activity can be completely and selectively rescued by transient cyclin D1 overexpression. Finally, we provide indirect evidence that the effect of melatonin on the cyclin D1 promoter is mediated by the c-jun and ATF-2 proteins, known to bind the minimal estrogen-sensitive cyclin D1 promoter element. These findings establish for the first time a molecular link between melatonin and its effects on the cell cycle, providing at the same time a rationale for its use in adjuvant chemotherapy.

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“…the accumulation of cells in the G 0 /G 1 phase of the cell cycle [34]. Although there are interesting findings in the combination of these two agents, there are only few studies which describe the synergistic effects of melatonin and tamoxifen in vitro and in vivo [35–38]. Herein, we studied the effects of melatonin in combination with either tamoxifen or ethanol on the proliferative activity of the mouse hepatoma cell line HEPA 1–6 [39].…”

Section: Introductionmentioning

confidence: 99%

Potentiation of antiproliferative effects of tamoxifen and ethanol on mouse hepatoma cells by melatonin: possible involvement of mitogen‐activated protein kinase and induction of apoptosis

Hermann

Podhajsky

Jungnickel

et al. 2002

Journal of Pineal Research

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Melatonin, the major secretory product of the pineal gland, is in focus of many research areas because of its ability to scavenge free oxygen radicals and thereby protect cells and tissues from radical damage. Some studies suggest melatonin may be a possible therapeutic agent with potential clinical applications against pathological states due to reactive oxygen species. Here, we investigated the effects of melatonin on the mouse hepatoma cell line HEPA 1-6, coincubated with ethanol, and tamoxifen, respectively. Cell proliferation rates were detected by the 3-[4,5 dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide (MTT) proliferation assay. A dose-dependent inhibition of the proliferative activity by melatonin was observed from 640 microM to 3 mM, which was significantly higher (P < 0.01) than with the solvent (ethanol) alone. Concentrations of 320 microM and less had no effect on cell proliferation. This antiproliferative effect might be because of the prolonged activation of mitogen-activated protein kinase which was activated by phosphorylation 15 min after the induction with melatonin. Furthermore, apoptosis was found to be enhanced by melatonin (75% more than with the solvent alone, P < 0.001). Finally, we show that the inhibitory effect of tamoxifen (25 microM) is markedly enhanced by the coincubation with melatonin (1.3 mM) up to 75% (P < 0.001). These data show that the antiproliferative effects of tamoxifen and ethanol, respectively, on mouse hepatoma cell line HEPA 1-6 are enhanced by melatonin. Although at the conditions described here the antiproliferative effects of melatonin occur at supraphysiological concentrations, these data may help to support clinical studies where melatonin is given simultaneously with tamoxifen or other standard chemotherapeutica.

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Combination of melatonin and tamoxifen as a chemoprophylaxis against N-nitroso-N-methylurea-induced rat mammary tumors

Cited by 21 publications

References 21 publications

The 1.5 GHz Electromagnetic Near‐field Used for Cellular Phones Does Not Promote Rat Liver Carcinogenesis in a Medium‐term Liver Bioassay

The 1.5 GHz Electromagnetic Near‐field Used for Cellular Phones Does Not Promote Rat Liver Carcinogenesis in a Medium‐term Liver Bioassay

Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin‐induced oncostatic effects

Potentiation of antiproliferative effects of tamoxifen and ethanol on mouse hepatoma cells by melatonin: possible involvement of mitogen‐activated protein kinase and induction of apoptosis

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