A two generation reproductive toxicity study with curcumin, turmeric yellow, in Wistar rats

Ganiger, Shivaputhrappa; Malleshappa, H.N.; Krishnappa, H.; Rajashekhar, G.; Rao, V. Ramakrishna; Sullivan, Frank

doi:10.1016/j.fct.2006.07.016

Cited by 91 publications

(75 citation statements)

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“…The studies using rats as animal models have shown that orally administered curcumin has no toxic effects on fertility or pregnancy in the fed rats, and no malformations were observed in their offspring. 13) In this report, we used zebrafish (Danio rerio) as model organisms to investigate the developmental toxicity of curcumin. Advantages of using zebrafish as model organisms include their small size (2-4 cm long), ease of breeding in the laboratory, light-induced fertilization, and sensitivity to environmental changes.…”

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Curcumin Affects Development of Zebrafish Embryo

Lin

et al. 2007

Biological & Pharmaceutical Bulletin

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Curcumin (diferuloylmethane) is a dietary polyphenol derived from the rhizomes of turmeric (Curcuma longa). For a long time, curcumin has been applied as an anti-inflammatory, 1) anti-oxidative, 2-4) and anti-carcinogenic 5) compound. The multiple therapeutic effects of curcumin result from its ability to modulate enzyme activities and gene expression. For example, curcumin has been shown to down-regulate the activities of several transcription factors, including NF-kappa B, AP-1, and Egr-1, as well as growth factor receptors such as EGFR and HER2. 6) Curcumin also inhibits the activities of COX2, LOX, iNOS, MMP-9, c-Jun N-terminal kinase, protein tyrosine kinases, and protein serine/threonine kinases. 6) Curcumin has been shown to repress expression of oncogenes such as c-fos, c-jun and c-myc, and suppress proliferation of tumour cells. [7][8][9] Finally, recent studies have demonstrated that curcumin can inhibit p300/CBP histone acetyltransferase activity both in vivo and in vitro. 10,11) p300/CBP transfers the acetyl group from an acetyl-CoA to conserved lysine residues in the histones, consequently, leading to transcription activity.12) Therefore, curcumin may modulate gene expression through inhibition of p300/CBP activities.Although the effects of curcumin on enzyme activities and gene expression have been studied in detail, only a few reports described its toxicity to embryos. The studies using rats as animal models have shown that orally administered curcumin has no toxic effects on fertility or pregnancy in the fed rats, and no malformations were observed in their offspring.13) In this report, we used zebrafish (Danio rerio) as model organisms to investigate the developmental toxicity of curcumin. Advantages of using zebrafish as model organisms include their small size (2-4 cm long), ease of breeding in the laboratory, light-induced fertilization, and sensitivity to environmental changes. Our results indicated that, unlike in rats, curcumin had embryotoxic and teratogenic effects on zebrafish embryos in a mM region. MATERIALS AND METHODS Collecting Fertilized Zebrafish EggsAdult zebrafish purchased from a local fish store were maintained in a laboratory under 28Ϯ1°C and a 14 h day/10 h night photoperiod.Fertilized eggs were collected within 30 min after natural mating, washed with sterile water, and placed in petri dishes.Curcumin Treatment and Embryos Observances Curcumin was purchased from Sigma Chemical (St. Louis, MO, U.S.A.), and dissolved in dimethyl sulfoxide (DMSO) to make a 25 mM stock solution. For embryo exposures, fertilized eggs were placed in 6-well petri dishes with ten embryos per well in 10 ml sterile water. Next, 30 ml of seriously diluted curcumin stock solutions was added to get final concentrations of 5, 7.5, 10, 12.5, and 15 mM. Thirty embryos were used for each of four replicates. The embryotoxic and teratogenic effects of resveratrol, quercetin, and rutin were also investigated in this study. Resveratrol, quercetin, and rutin were all purchased from Sigma Chemical (St. Louis, MO...

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Curcumin Affects Development of Zebrafish Embryo

Lin

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Advantages of using zebrafish as model organisms include their fecundity, optical clarity, and genetic similarity to mammals. Research using rats as animal models revealed that orally administered curcumin had no toxic effects on fertility or pregnancy (24). Our findings have shown that, unlike in rats, liposomal curcumin had embryotoxic and anti-angiogenic effects on the development of zebrafish embryos.…”

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Liposomal curcumin inhibits Lewis lung cancer growth primarily through inhibition of angiogenesis

Wang¹,

Zhang

Cai

et al. 2012

Oncology Letters

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Abstract. Curcumin has been proven to effectively inhibit tumor growth by both targeting tumor cells and angiogenesis; however, poor water solubility limits further clinical application. In the present study, we prepared water-soluble liposomal curcumin to investigate its anti-tumor effects and the underlying mechanism. The MTT assay was used to test the anti-proliferative activities for the MS1 murine endothelial and LL/2 Lewis lung cancer cell lines. Apoptosis and cell cycle arrest induced by liposomal curcumin were analysed by flow cytometry. Anti-angiogenic agents and the resulting anti-tumor effects were investigated in a murine lung cancer model. Zebrafish were used to investigate the anti-angiogenic effect of liposomal curcumin in the development of embryos. In vitro, liposomal curcumin inhibited the proliferation of MS1 cells and induced cell cycle arrest and apoptosis. Notably, LL/2 cells showed less sensitivity to the liposomal curcumin in vitro. In vivo, the systemic administration of liposomal curcumin resulted in significant inhibition of tumor growth. CD31 immunohistochemical analysis and alginate encapsulation assay revealed that angiogenesis was decreased by liposomal curcumin treatment. Angiogenesis was also suppressed in the development of zebrafish. Liposomal curcumin showed potent inhibitory activity against murine endothelial cells but not lung cancer cells. Liposomal curcumin treatment is capable of significantly inhibiting tumor growth in vivo, a process that may depend primarily on its anti-angiogenic effects. Our study also indicates that liposomal curcumin may be developed not only for cancer therapy, but also for the treatment of other angiogenesis-related diseases. IntroductionCurcumin has been proven to be a promising anti-cancer drug by induction of apoptosis and apoptosis-independent death, and inhibition of proliferation and angiogenesis (1-4). Phase I and II studies of this compound have shown that curcumin is well tolerated and is effective for cancer patients; however, its benefits may be attenuated due to its low bioavailability through oral administration for non-gastrointestinal cancers (5,6). Therefore, novel strategies are required to overcome these limitations, which are mostly due to the low water solubility and low stability of curcumin against gastrointestinal fluids (7). Investigators have recognized that liposomes have the advantage of improving water insolubility and enhancing delivery efficacy of drugs (8). At present, various methods have been reported for the preparation of liposomes (9). Curcumin acts as an anticancer drug through multiple mechanisms; however, the activity of curcumin may be changed in a liposomal form. Furthermore, the water solubility of liposomal curcumin provides a new strategy for intravenous administration. It is speculated that, systemically, intravenous administration may exhibit marked inhibitory effects due to circumvention of the first-pass effect. Angiogenesis, the process by which capillaries sprout from pre-existing vasculature, is...

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“…Araştırmacılar, bu çalışma sonucuna göre kurkuminin üreme parametreleri üzerinde herhangi bir olumsuz toksikolojik etkisinin olmadığını ve üreme toksisitesi için NOAEL değerini 10.000 ppm (=erkek sıçanlarda 847-959 mg/kg, dişi sıçanlarda 1.043-1.076 mg/kg eşdeğer-dir) olarak belirlemişlerdir. 85 …”

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