Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling

Abstract

Melatonin is known to exert antitumour activity in several types of human cancers, but the underlying mechanisms as well as the efficacy of different doses of melatonin are not well defined. Here, we test the hypothesis whether melatonin in the nanomolar range is effective in exerting antitumour activity in vivo and examine the correlation with the hypoxia signalling mechanism, which may be a major molecular mechanism by which melatonin antagonizes cancer. To test this hypothesis, LNCaP human prostate cancer cells were xenografted into seven-wk-old Foxn1nu/nu male mice that were treated with melatonin (18 i.p. injections of 1 mg/kg in 41 days). Saline-treated mice served as control. We found that the melatonin levels in plasma and xenografted tissue were 4× and 60× higher, respectively, than in control samples. Melatonin tended to restore the redox imbalance by increasing expression of Nrf2. As part of the phenotypic response to these perturbations, xenograft microvessel density was less in melatonin-treated animals, indicative of lower angiogenesis, and the xenograft growth rate was slower (P < 0.0001). These changes were accompanied by a reduced expression of Ki67, elevated expression of HIF-1α and increased phosphorylation of Akt in melatonin than saline-treated mice. We conclude that the beneficial effect of melatonin in reducing cancer growth in vivo was evident at melatonin plasma levels as low as 4 nm and was associated with decreased angiogenesis. Higher HIF-1α expression in xenograft tissue indicates that the antitumour effect cannot be due to a postulated antihypoxic effect, but may stem from lower angiogenesis potential.

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

“…Notably, previous findings have shown a role for melatonin in preventing tumor initiation and progression (28)(29)(30)(31)(32)(33)(34). Specifically, melatonin was reported to inhibit cell proliferation and induce apoptosis in osteosarcoma (35), B-lymphoma (36) and colorectal cancer cells (37), as well as to decrease the weight of tumor masses in breast and prostate cancer (38)(39)(40). Based on those reports, the present study was conducted to examine the effects of melatonin on RMS cell lines in vitro.…”

Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer

“…Body weight and tumor volume were measured three times a week for 42 days. At the end of the observation period, mice were anesthetized, thoracotomized to withdraw a blood sample, and tumors were quickly excised from surrounding skin and frozen as described (Paroni et al, 2014). Figure 1 shows the flowchart of the experimental design.…”

“…injections of 1 mg/kg melatonin for 42 days, 3 injections/ week), the growth of LNCaP prostate cancer was reduced 4-fold compared to saline-treated control (Paroni et al, 2014). The marked antitumor activity of melatonin even without association with any other drug calls the opportunity to investigate novel roads for alternative painless and noninvasive ways of administering this substance to improve the sustainability of such therapy for long-term treatments.…”

“…Melatonin has paracrine, autocrine as well as antioxidant effects, and exerts diverse receptor-dependent and receptor-independent actions, with overall homeostatic functions and pleiotropic effects relevant to cell protection and survival (Srinivasan et al, 2008;Luchetti et al, 2010). Melatonin is known to display oncostatic activity in a variety of tumors including breast (Mao et al, 2016), ovarian (Zhao et al, 2016), colon (Gao et al, 2016), endometrial (Ciortea et al, 2011), gastrointestinal (Wang et al, 2016b), and prostate (Paroni et al, 2014). The link between plasma melatonin and prostate cancer risk is well recognized.…”

Perspectives of Melatonin Use in Clinical Oncology

“…МЛТ обладает способ-ностью потенцировать эффект цитостатиков и оказывает значительное влияние на иммунную систему [15,16]. Это достигается благодаря различным механизмам сдержи-вания опухолевого роста -активации и переориентации иммунного ответа в сторону Т-хелперов 1 типа и увели-чению продукции ряда цитокинов (IL-2, IFN-, интерлей-кина-6) [17,18], снижению экспрессии VEGF рецептора [19], активации апоптоза в опухолевых клетках [20][21][22][23], уменьшению активности теломеразы [24]. Прослежена корреляция между противоопухолевым действием МЛТ и уровнем экспрессии МТ 1 рецепторов в клетках опухо-ли [24].…”