DNA damage and repair in human peripheral blood lymphocytes following treatment with microcystin-LR

Lankoff, Anna; Krzowski, Łukasz; Głab, Joanna; Banasik, Anna; Lisowska, Halina; Kuszewski, Tomasz; Góźdż, Stanisław; Wójcik, Andrzej

doi:10.1016/j.mrgentox.2004.01.004

Cited by 72 publications

(43 citation statements)

References 53 publications

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“…In lymphocytes in vitro, the mechanism of microcystin toxicity was associated with free radical formation; in those studies, cells were exposed to micromolar concentrations of microcystin LR (26,27), in comparison with the subnanomolar range in the transfected HeLa cells.…”

Section: Discussionmentioning

confidence: 99%

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Liu

et al. 2007

Molecular Cancer Therapeutics

147

126

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Microcystins are a family of cyclic peptides that are potent inhibitors of the protein phosphatase families PP1 and PP2A. Only three human proteins are thought to be able to mediate the hepatic uptake of microcystins (the organic anion-transporting polypeptides OATP1B1, OATP1B3, and OATP1A2), and the predominant hepatic expression of these transporters accounts for the liver-specific toxicity of microcystins. A significant obstacle in the study of microcystins as anticancer drugs is the requirement of specific transport proteins for cellular uptake. We report that OATP1B3 mRNA is up-regulated in non -small cell lung cancer tumors in comparison with normal control tissues. This finding led to the exploration of microcystins as potential anticancer agents. We have developed a HeLa cell model with functional OATP1B1 and OATP1B3 activity. Transiently transfected HeLa cells are over 1,000-fold more sensitive to microcystin LR than the vector-transfected control cells, showing that transporter expression imparts marked selectivity for microcystin cytotoxicity. In addition, microcystin analogues showed variable cytotoxicities in the OATP1B1-and OATP1B3-transfected cells, including two analogues with IC 50 values <1 nmol/L. Cytotoxicity of microcystin analogues seems to correlate to the inhibition of PP2A in these cells and induces rapid cell death as seen by chromatin condensation and cell fragmentation. These studies show that microcystin-induced phosphatase inhibition results in potent cytotoxicity when microcystin compounds can gain intracellular access and are a potent novel class of therapeutic agents for tumors expressing these uptake proteins. [Mol Cancer Ther 2007;6(2):587 -98]

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Section: Discussionmentioning

confidence: 99%

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Liu

et al. 2007

Molecular Cancer Therapeutics

147

126

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“…Several mutagenicity studies excluded the hypothesis of MCLR being a mutagen [49,50], which was further supported by the fact that MCLR do not form adducts with DNA that would represent a pre-mutagenic lesion [51]. On the other hand, some authors reported that MCLR-induced DNA damage was a consequence of early apoptosis due to oxidative stress and not a real genotoxic effect [52]. This hypothesis was supported by the discovery that MCLR induces the formation of 8-oxo-dG, a marker of oxidative DNA damage in liver cells [51].…”

Section: Genotoxicitymentioning

confidence: 99%

“…Some authors have also proposed that MCLR might interfere with DNA repair processes, namely the repair of gamma radiation and ultra-violet-induced DNA damage [52,54,57], thus increasing the genotoxic potency of those agents and contributing to their carcinogenesis. In our early studies with the Vero-E6 cell line we demonstrated that cyanobacterial extracts from a MCLR-producer cyanobacterial strain increased the frequency of micronuclei at noncytotoxic concentrations [26].…”

Section: Genotoxicitymentioning

confidence: 99%

The Kidney Vero-E6 Cell Line: A Suitable Model to Study the Toxicity of Microcystins

Menezes¹,

Valério²,

Dias³

2013

New Insights Into Toxicity and Drug Testing

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“…This view was corroborated by the findings of Sano et al (2004), who expressed the opinion that MC-LR induces lipid peroxidative reactions and thus, oxidative DNA damage (mainly 8-OH-dG) but not DNA adducts. A study by Lankoff et al (2004) suggested that MC-LR-induced DNA damage may be related to the early stages of apoptosis due to cytotoxicity but not genotoxicity and that MC-LR reduces the capability of DNA repair in human peripheral lymphocytes following UV damage. However, due to the use of relatively high doses of MC-LR, the relevance of these results is somewhat questionable.…”

Section: Genotoxicitymentioning

confidence: 99%

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

Dietrich

Hoeger

2005

Toxicology and Applied Pharmacology

325

185

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This article reviews current scientific knowledge on the toxicity and carcinogenicity of microcystins and compares this to the guidance values proposed for microcystins in water by the World Health Organization, and for blue-green algal food supplements by the Oregon State Department of Health. The basis of the risk assessment underlying these guidance values is viewed as being critical due to overt deficiencies in the data used for its generation: (i) use of one microcystin congener only (microcystin-LR), while the other presently known nearly 80 congeners are largely disregarded, (ii) new knowledge regarding potential neuro and renal toxicity of microcystins in humans and (iii) the inadequacies of assessing realistic microcystin exposures in humans and especially in children via blue-green algal food supplements. In reiterating the state-of-the-art toxicology database on microcystins and in the light of new data on the high degree of toxin contamination of algal food supplements, this review clearly demonstrates the need for improved kinetic data of microcystins in humans and for discussion concerning uncertainty factors, which may result in a lowering of the present guidance values and an increased routine control of water bodies and food supplements for toxin contamination. Similar to the approach taken previously by authorities for dioxin or PCB risk assessment, the use of a toxin equivalent approach to the risk assessment of microcystins is proposed. D

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DNA damage and repair in human peripheral blood lymphocytes following treatment with microcystin-LR

Cited by 72 publications

References 53 publications

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells

The Kidney Vero-E6 Cell Line: A Suitable Model to Study the Toxicity of Microcystins

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

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