Studies on the effects of the pineal hormone melatonin on an androgen-insensitive rat prostatic adenocarcinoma, the Dunning R 3327 HIF tumor

Gr, Buzzell

doi:10.1007/bf01250236

Cited by 17 publications

(4 citation statements)

References 20 publications

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“…96 In these animals, late afternoon injections of melatonin significantly inhibited the growth of androgen-sensitive prostatic tumors. The mechanism through which melatonin induces tumor suppression in prostate cells was then studied.…”

Section: Melatonin and Prostate Cancermentioning

confidence: 89%

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

et al. 2008

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189predisposing factors for the development of cancer in humans.2,3 A recent study involving 44 000 pairs of Scandinavian twins suggested that environmental factors are paramount contributors in cancer development. 4 The human body is well equipped with both immune and nonimmune anticarcinogenic mechanisms for fighting cancer. Natural killer (NK) lymphocytes play an important role in inhibiting tumor growth and metastases. 5 Many studies implicate oxidative stress in precipitating the 3 steps of carcinogenesis, that is, its initiation, promotion, and progression.6 Free radicals and reactive oxygen species (ROS) generated by environmental carcinogens, or by metabolic alterations, cause DNA damage and genetic instability. [6][7][8] DNA damage induced by oxidative stress is the major contributor to the development of malignancy. It is wellknown that natural antioxidant defenses are active in counteracting the production of free radicals and the molecular damage inflicted by them on DNA and other C ancer is a major health problem in industrialized and developing countries. Most diagnoses of cancer occur in people more than 55 years of age, with prostate cancer being the leading type of cancer in males followed by lung cancer. In females, breast and colon cancers are the leading types of cancer. Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth inhibitory effects on breast cancer cell lines. In hepatomas, through its activation of MT 1 and MT 2 receptors, melatonin inhibits linoleic acid uptake, thereby preventing the formation of the mitogenic metabolite 1,3-hydroxyoctadecadienoic acid. In animal model studies, melatonin has been shown to have preventative action against nitrosodiethylamine (NDEA)-induced liver cancer. Melatonin also inhibits the growth of prostate tumors via activation of MT 1 receptors thereby inducing translocation of the androgen receptor to the cytoplasm and inhibition of the effect of endogenous androgens. There is abundant evidence indicating that melatonin is involved in preventing tumor initiation, promotion, and progression. The anticarcinogenic effect of melatonin on neoplastic cells relies on its antioxidant, immunostimulating, and apoptotic properties. Melatonin's oncostatic actions include the direct augmentation of natural killer (NK) cell activity, which increases immunosurveillance, as well as the stimulation of cytokine production, for example, of interleukin (IL)-2, IL-6, IL-12, and interferon (IFN)-γ. In addition to its direct oncostatic action, melatonin protects hematopoietic precursors from the toxic effect of anticancer chemotherapeutic drugs. Melatonin secretion...

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Section: Melatonin and Prostate Cancermentioning

confidence: 89%

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

et al. 2008

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“…A direct interaction between melatonin and prostate cancer was previously proposed, although controversial results have been reported. Melatonin has been shown to inhibit the growth of R3327H Dunning prostate adenocarcinoma [22] but to enhance the growth of a transplantable androgen-insensitive prostatic adenocarcinoma in rats [23]. Physiological concentrations of the hormone inhibit 3 H-thymidine incorporation in androgen-sensitive LNCaP prostate cancer cells [24]; in androgen-insensitive PC3 prostate cancer cells, melatonin differently affects 3 H-thymidine incorporation according to cell density [25], stimulating it at low cell density and attenuating it in high-density cultures [25].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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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.

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“…However, further analysis found that, while afternoon melatonin administration induced tumor remission in castrated rodents, continuous melatonin administration did not have any significant effect on CaP tumors (Buzzell 1988), suggesting that melatonin is only effective when administered in synchronization with the patient’s natural circadian cycle,. Further, the study also emphasized that melatonin is more effective with low AR activity.…”

Section: Melatonin Regulation Of Prostate Carcinogenesismentioning

confidence: 96%

WOMEN IN CANCER THEMATIC REVIEW: Circadian rhythmicity and the influence of ‘clock’ genes on prostate cancer

Kiss

Ghosh

2016

Endocrine-Related Cancer

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The androgen receptor (AR) plays a key role in the development and progression of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out higher incidences of CaP in some select groups, such as airline pilots and night shift workers in comparison to those working regular hours. The common finding in these “high-risk” groups was that they all experienced a deregulation of the body’s internal circadian rhythm. Here we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumor suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT). In addition, a large-scale study found that high-dose radiation was more effective in CaP patients when it was delivered before 5PM, compared to those delivered after 5PM, suggesting that the therapy was more effective when delivered in synchrony with the patient’s circadian clock. As CaP patients are shown to become easily resistant to new therapies, perhaps circadian delivery of these therapeutic agents or delivery in conjunction with melatonin and its novel analogs should be tested to see if they prevent this resistance.

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Studies on the effects of the pineal hormone melatonin on an androgen-insensitive rat prostatic adenocarcinoma, the Dunning R 3327 HIF tumor

Cited by 17 publications

References 20 publications

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms

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

WOMEN IN CANCER THEMATIC REVIEW: Circadian rhythmicity and the influence of ‘clock’ genes on prostate cancer

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