Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

Taketa, Yoshikazu; Inoue, Kaoru; Takahashi, Miwa; Sakamoto, Yohei; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

doi:10.1002/jat.3206

Cited by 5 publications

(7 citation statements)

References 42 publications

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“…As sulpiride has been shown to inhibit gastric carcinogenesis (Tatsuta et al, 1991) as well as endometrial carcinogenesis (Taketa et al, 2016) in rats, it would be interesting to further test how the potential of sulpiride in inhibiting liver carcinogenesis and how DAPK1 may be involved in future study.…”

Section: Discussionmentioning

confidence: 99%

DAPK1 as an independent prognostic marker in liver cancer

Guo

Wang

et al. 2017

PeerJ

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The death-associated protein kinase 1 (DAPK1) can act as an oncogene or a tumor suppressor gene depending on the cellular context as well as external stimuli. Our study aims to investigate the prognostic significance of DAPK1 in liver cancer in both mRNA and protein levels. The mRNA expression of DAPK1 was extracted from the Gene Expression Omnibus database in three independent liver cancer datasets while protein expression of DAPK1 was detected by immunohistochemistry in our Chinese liver cancer patient cohort. The associations between DAPK1 expression and clinical characteristics were tested. DAPK1 mRNA expression was down-regulated in liver cancer. Low levels of DAPK1 mRNA were associated with shorter survival in a liver cancer patient cohort (n = 115; p = 0.041), while negative staining of DAPK1 protein was significantly correlated with shorter time to progression (p = 0.002) and overall survival (p = 0.02). DAPK1 was an independent prognostic marker for both time to progression and overall survival by multivariate analysis. Liver cancer with the b-catenin mutation has a lower DAPK1 expression, suggesting that DAPK1 may be regulated under the b-catenin pathway. In addition, we also identified genes that are co-regulated with DAPK1. DAPK1 expression was positively correlated with IRF2, IL7R, PCOLCE and ZBTB16, and negatively correlated with SLC16A3 in both liver cancer datasets. Among these genes, PCOLCE and ZBTB16 were significantly down-regulated, while SLC16A3 was significantly upregulated in liver cancer. By using connectivity mapping of these co-regulated genes, we have identified amcinonide and sulpiride as potential small molecules that could potentially reverse DAPK1/PCOLCE/ZBTB16/SLC16A3 expression. Our study demonstrated for the first time that both DAPK1 mRNA and protein expression levels are important prognostic markers in liver cancer, and have identified genes that may contribute to DAPK1-mediated liver carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

DAPK1 as an independent prognostic marker in liver cancer

Guo

Wang

et al. 2017

PeerJ

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“…The specific mechanism of this has not yet been determined; however, the primary MOA was thought to be a decreased E2 to P4 ratio due to the modulation of P4 production by prolactin. Our current work provided interesting evidence demonstrating that short- and long-term treatment with sulpiride, a typical dopamine antagonist, clearly increased serum prolactin 25 and inhibited uterine tumor development 26 . In addition, long-term treatment with sulpiride also decreased the E2 to P4 ratio, indicating that prolactin has various complex functions.…”

Section: Discussionmentioning

confidence: 57%

Predictive modes of action of pesticides in uterine adenocarcinoma development in rats

2015

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Endometrial adenocarcinoma in the uterine corpus is a malignant cancer that occurs in menopausal women and aged rodents. Because of the similarities in pathogenesis and morphology of endometrial adenocarcinoma in rodents and humans, prediction of the modes of action (MOA) in uterine carcinogenesis is important for extrapolation of rodent data to humans. Three MOAs have been accepted as major pathways for uterine carcinogenesis in rodents: 1) estrogenic activity, 2) increased serum 17beta-estradiiol (E2) to progesterone (P4) ratio and 3) modulation of estrogen metabolism to produce 4-hydroxyestradiol via P450 induction. Inhibition of estrogen excretion and increased aromatase in situ in the tumor are also a potential pathway. Here, chemicals showing uterine carcinogenicity were chosen from approximately 300 pesticides evaluated in Japan within the past decade, and their mechanisms were predicted using parameters from mechanistic and toxicity studies. Seven pesticides increased uterine tumor formation in rats, and the pathways of 4 pesticides could be predicted based on various mechanistic studies. The MOAs of cyenopyrafen and benthiavalicarb-isopropyl were predicted to be modulation of estrogen metabolism, while those of pyriminobac-methyl and spirodiclofen were predicted to be increased E2 to P4 ratio. The driven pathways of metazosulfuron and isopyrazam could not be predicted using several mechanistic studies. No mechanistic studies have been reported for sedaxane, which has a chemical structure and toxicological profile similar to isopyrazam. Our results indicated that appropriate mechanistic studies are useful for mechanism prediction in risk assessment. From this analysis, a flowchart showing a decision tree for predictive MOAs in uterine carcinogenesis was proposed.

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“…The antifertility effects described for PAs and the identification of PAs in the Emilia genus strongly implicates compound 5 as a potential compound for further study as the active constituent responsible for the antifertility effects observed in this study. Glycols have been reported to exhibit antitumor effects (Wang et al 1996;Taketa et al 2015), anxiolytic effects (Lin et al 1998), and sedative effects in humans (Singh et al 1981;Forrest and Galletly 1988). Reports have shown polyethylene glycol (PEG) to exert inhibitory effects on liver enzymes and on central nervous system activity (Nishimura et al 1998;Thomsen et al 1995).…”

Section: Chromatogram and Biological Effects Of Identified Compoundsmentioning

confidence: 99%

In vivo investigation of female reproductive functions and parameters in nonpregnant mice models and mass spectrometric analysis of the methanol leaf extract ofEmilia Coccinea(Sims) G Dons

et al. 2016

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In Southern Nigeria, the leaves of Emilia coccinea (Sims) G Dons are used traditionally for birth control. This study was therefore aimed at evaluating the activities of the methanolic leaf extract of Emilia coccinea (EM) on parameters that affect reproduction as well as the acute toxic effects of the plant using nonpregnant female mice models. Leaves of EM were extracted by maceration with 99.8% methanol. Oral acute toxicity profiles were examined. The effects of EM on female reproductive cycle were determined after oral treatment with EM at 1000 and 100 mg/kg/day daily for 6 days using stilbesterol (1 mg/kg/day) and normal saline as controls. The activities of EM (1000 mg/kg/day and 100 mg/kg/day p.o) on reproductive hormones and organs were also studied using estradiol valerat (100 mg/kg/day p.o), progesterone (10 mg/kg/day s.c.), and normal saline as controls. The extract did not induce any observable toxic effect after 24 h. At 1000 mg/kg, the extract significantly shortened the estrus cycle (P < 0.05) while prolonging the estrus phase which were comparable to that observed with stilbesterol. The extract also increased uterine weight and altered the histology of uterine and ovarian tissues. The female reproductive hormones were additionally altered at 1000 mg/kg and the effects were comparable to that of estradiol valerat such as to indicate possible antifertility effects. LC‐HRFTMS analysis showed 9 putatively identified compounds with pyrrolizidine alkaloid occurring at the highest intensity among the identified compounds. In conclusion, the leaf extracts of EM has been shown in this study to exhibit antiovulatory and estrogenic activities which would support the traditional use of the plant in Nigeria.

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Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats

Cited by 5 publications

References 42 publications

DAPK1 as an independent prognostic marker in liver cancer

DAPK1 as an independent prognostic marker in liver cancer

Predictive modes of action of pesticides in uterine adenocarcinoma development in rats

In vivo investigation of female reproductive functions and parameters in nonpregnant mice models and mass spectrometric analysis of the methanol leaf extract ofEmilia Coccinea(Sims) G Dons

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