Abstract：
:Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.
journal_name
J Pineal Resjournal_title
Journal of pineal researchauthors
Ju HQ,Li H,Tian T,Lu YX,Bai L,Chen LZ,Sheng H,Mo HY,Zeng JB,Deng W,Chiao PJ,Xu RHdoi
10.1111/jpi.12285subject
Has Abstractpub_date
2016-01-01 00:00:00pages
27-38issue
1eissn
0742-3098issn
1600-079Xjournal_volume
60pub_type
杂志文章abstract：:The objective of this study was to apply the radioimmunoassay for 6-sulphatoxymelatonin (aMT6s) to rat urine, and use it to study the source of aMT6s. The radioimmunoassay was found to have acceptable within- and between-assay variation, excellent specificity, and good parallelism between the standard and unknown. Bec...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1991.tb00831.x
更新日期：1991-04-01 00:00:00
abstract：:Melatonin is known to regulate a variety of physiological processes including control of circadian rhythms, regulation of seasonal reproductive function, regulation of body temperature, and so forth. Accumulating evidence from in vitro and in vivo experiments using rodent and chicken has also suggested that melatonin ...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2006.00410.x
更新日期：2007-04-01 00:00:00
abstract：:Although there is an increasing evidence that the pineal gland may play a role in human malignancy, the studies on melatonin concentrations in different types of malignant tumors brought about controversial results. However, changes in melatonin concentrations have been observed in some types of human malignant tumors...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2005.00221.x
更新日期：2005-08-01 00:00:00
abstract：:Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin-medi...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/jpi.12365
更新日期：2016-11-01 00:00:00
abstract：:Melatonin has been shown to have a direct inhibitory action on the proliferation of estrogen-responsive MCF-7 human breast cancer cells in culture. In the present study, we examined by flow cytometry whether this inhibitory effect might be exerted on the G1 phase of the cell cycle, thus causing a transition delay into...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1991.tb00007.x
更新日期：1991-01-01 00:00:00
abstract：:Studies on farm animals have contributed significantly to our increased understanding of basic melatonin-related physiological mechanisms, as well as to the regulation of reproduction and pelage in individual domestic species. This review concentrates on recent work on the role of melatonin in the regulation of porcin...
journal_title：Journal of pineal research
pub_type： 杂志文章,评审
doi：10.1111/j.1600-079x.1994.tb00097.x
更新日期：1994-05-01 00:00:00
abstract：:Resistance inducers are a class of agrochemicals, including benzothiadiazole and chitosan, which activate the plant own defence mechanisms. In this work, open-field treatments with plant activators were performed on two red grape (Vitis vinifera L.) varieties cultivated in different localities, Groppello (Brescia, Lom...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2011.00887.x
更新日期：2011-10-01 00:00:00
abstract：:There are functional inter-relationships between the beta cells of the endocrine pancreas and the pineal gland, where the synchronizing circadian molecule melatonin originates. The aim of this study was to elucidate a putative interaction between insulin and melatonin in diabetic patients and a diabetic rat model. We ...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2005.00287.x
更新日期：2006-03-01 00:00:00
abstract：:Production of melatonin in the pineal gland of inbred mice such as C57B1/6J, BALB/c and AKR strains is still a matter of debate. In previous studies, we and other authors showed that these strains of inbred mice have a clear-cut circadian rhythm of serum melatonin and urinary 6-hydroxy-melatonin-sulphate. In contrast,...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1996.tb00249.x
更新日期：1996-04-01 00:00:00
abstract：:Doxorubicin (DOX) and Trastuzumab (TRAST) are effective agents for the treatment of many neoplastic diseases. Cardiotoxicity is a major side effect of these drugs and limit their use. In this study, the possible protective effects of melatonin (MEL), mercaptoethylguanidine (MEG), or N-(3-(aminomethyl) benzyl) acetamid...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2010.00818.x
更新日期：2011-01-01 00:00:00
abstract：:In the mammalian pineal gland, the rhythm in melatonin biosynthesis depends on the norepinephrine (NE)-driven regulation of arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme of melatonin biosynthesis. A recent study showed that phytocannabinoids like tetrahydrocannabinol reduce AANAT activity and atte...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2008.00597.x
更新日期：2008-11-01 00:00:00
abstract：:Melatonin is part of the evolutionary conserved highly functional network in vertebrates. It plays a central role in the adaptative behavior of the animal to the environment, including entrainment of daily and annual physiological rhythms, reproductive behavior, food intake, locomotor activity, growth, and breeding pe...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/jpi.12149
更新日期：2014-08-01 00:00:00
abstract：:Glaucoma may be associated with circadian disruption due to its association with a loss of intrinsically photosensitive retinal ganglion cells. Clinical evidence demonstrating an association between glaucoma and circadian disruption is limited, and no large-scale studies have been performed. The purpose of this cross-...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/jpi.12662
更新日期：2020-09-01 00:00:00
abstract：:It has been suggested that oxidative stress is a feature of aging. The goal of the present study was to assess the oxidant effects related to aging and the protective role of exogenous melatonin in senescence-accelerated mice (SAMP8). Two groups of SAMP8 mice (males and females) were compared with their respective con...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2006.00344.x
更新日期：2006-09-01 00:00:00
abstract：:The circadian system comprises several peripheral oscillators and a central rhythm generator that, in mammals, is located in the suprachiasmatic nucleus of the hypothalamus. Expression of clock genes is a characteristic feature of the central rhythm generator and the peripheral oscillators. With regard to the rhythmic...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2005.00279.x
更新日期：2006-01-01 00:00:00
abstract：:To examine the role of melatonin in pathological hyperprolactinemia we compared untreated young females (N = 5) with hyperprolactinemic amenorrhea owing to pituitary microadenoma to healthy female controls (N = 6). Serum samples for melatonin, prolactin, and luteinizing hormone (LH) concentrations were obtained every ...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1996.tb00242.x
更新日期：1996-03-01 00:00:00
abstract：:The milk-ejecting response of lactating mouse mammary gland tissue to ovine pineal extracts indicated the presence of a neurohormone-like bioactivity in this tissue. After successive fractionation on gel permeation chromatography and reversed-phase liquid chromatography (HPLC) in conjunction with radioimmunoassays (RI...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1988.tb00800.x
更新日期：1988-01-01 00:00:00
abstract：:Melatonin has been shown to improve in vitro fertilization and offspring survival after bacterial infection, but its role in regulating maternal-fetal communication during early pregnancy has not been investigated. Results of this study demonstrated expression of abundant melatonin receptors in conceptus and endometri...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/jpi.12670
更新日期：2020-09-01 00:00:00
abstract：:Melatonin is a powerful scavenger of oxygen free radicals. In humans, melatonin is rapidly transferred from the maternal to the fetal circulation. To investigate whether or not maternal melatonin administration can protect the fetal rat brain from radical-induced damage by increasing the activities of antioxidant enzy...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1034/j.1600-079x.2001.280204.x
更新日期：2000-03-01 00:00:00
abstract：:Despite state-of-the-art pharmaceutical regimens, continuous improvements in diagnostic techniques as well as refinements in equipment and interventional procedures, many diseases remain refractory to conventional therapies. Recent advances in stem cell (SC) biology have opened an avenue to exploring its therapeutic p...
journal_title：Journal of pineal research
pub_type： 杂志文章,评审
doi：10.1111/jpi.12372
更新日期：2017-03-01 00:00:00
abstract：:We previously reported that pharmacological melatonin administration to type 2 diabetic rats reduces hyperinsulinemia and improves the altered fatty-acid metabolism. To determine whether melatonin deficiency exacerbates diabetes-associated conditions, we investigated the effect of pinealectomy (i.e. melatonin-deficien...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1034/j.1600-079x.2003.00083.x
更新日期：2003-11-01 00:00:00
abstract：:By use of Phaseolus vulgaris-leucoagglutinin as an anterograde in vivo tracer, a direct projection from the dorsal raphe nucleus to the pineal complex of the rat was demonstrated. The nerve fibers extended from the dorsal raphe nucleus rostrally through the mesencephalic periaqueductal grey and entered the deep pineal...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1998.tb00381.x
更新日期：1998-08-01 00:00:00
abstract：:During the past decade, a number of reports indicated that the mammalian pineal gland is magnetosensitive in terms of spatial orientation. This indication is based on observations that artificial alterations of the direction of the earth's magnetic field (MF) markedly decreased the gland's capability to synthesize mel...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1991.tb00826.x
更新日期：1991-04-01 00:00:00
abstract：:The production of oxygen free radicals has been strongly implicated as an important pathophysiological mechanism mediating myocardial ischemia/reperfusion (I/R) injury. Various antioxidants have cardioprotective effects. Melatonin, an indoleamine synthesized by the pineal gland, is a potent antioxidant and a direct fr...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1034/j.1600-079x.2002.01869.x
更新日期：2002-09-01 00:00:00
abstract：:Four weeks of administration of melatonin mixed in the diet (5 mg/kg of food) significantly reduced the incidence of gastric ulcers in young pigs. In control and melatonin supplemented animals, significantly higher levels of melatonin were found in the stomach tissues as compared to jejunum, ileum, or colon. Pigs with...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1998.tb00367.x
更新日期：1998-01-01 00:00:00
abstract：:Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. Howeve...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/jpi.12421
更新日期：2017-10-01 00:00:00
abstract：:In healthy young men, administration of a single light pulse (5000 lux for 3 hr) or a single melatonin pill (5 mg) at 20:40 hr under controlled constant routine conditions of <10 lux, yielded a phase delay and a phase advance, respectively, in the circadian marker of dim light melatonin onset 24 hr later. Phase shifts...
journal_title：Journal of pineal research
pub_type： 临床试验,杂志文章
doi：10.1111/j.1600-079x.2004.00117.x
更新日期：2004-04-01 00:00:00
abstract：:The distribution of nerve fibers immunoreactive (IR) to catecholamine-synthesizing enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H), and phenylethanolamine-N-methyltransferase (PNMT) as well as neuropeptide Y (NPY), in the pineal gland of adult sows was investigated by the use of double-labelin...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1994.tb00109.x
更新日期：1994-08-01 00:00:00
abstract：:The effects of melatonin (3 mg/kg i.p.) and the melatonin receptor agonist S-20098 (3 mg/kg i.p.) on the vigilance states, electroencephalogram power spectra (0.25-25.0 Hz), and cortical temperature were determined in eight rats in the first 6-hr interval of the 12-hr light period. Compared to the vehicle injection bo...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079x.1994.tb00078.x
更新日期：1994-01-01 00:00:00
abstract：:Melatonin, the main secretary product of the pineal gland, is potentially effective in the prevention of a number of diseases in which free radical processes are involved. The development of hypercholesterolemia is a multifactorial process in which elevated oxidized low-density lipoprotein (ox-LDL) levels play a centr...
journal_title：Journal of pineal research
pub_type： 杂志文章
doi：10.1111/j.1600-079X.2008.00595.x
更新日期：2008-10-01 00:00:00
