Clastogenicity of Aporphine Alkaloids in Vitro.

Tadaki, Shinichi; Nozaka, Tomio; Yamada, Shoichi; Ishino, Masazo; Morimoto, Isao; Tanaka, Akio; Kunitomo, Jun-ichi

doi:10.1248/bpb1978.15.501

Cited by 15 publications

(4 citation statements)

References 26 publications

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“…Genotoxic effects were generally proportional to alkaloid concentration. The genotoxicity of these alkaloids is in accord with results observed in earlier studies with other alkaloids that act as topoisomerase inhibitors, such as ellipticine, etoposide VP-16, daunorubicin, and idarubicin (evaluated through SMART in wing cells of D. melanogaster) [17][18][19], as well as dicentrine and liriodenine (using the Ames Test) [20,21]. Doxorubicin (DXR) was selected as a positive control in the present study because it induces DNA strand breaks by topoisomerase II inhibition [22].…”

Section: Discussionsupporting

confidence: 86%

Mutagenicity and recombinagenicity of Ocotea acutifolia (Lauraceae) aporphinoid alkaloids

Guterres

Silva

Garcez

et al. 2013

Mutation Research/Genetic Toxicology and Environmental Mutagene

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The somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster was used to test the mutagenic and recombinogenic activities of five aporphinoid alkaloids isolated from Ocotea acutifolia: thalicminine (1), (+)-dicentrine (2), (+)-ocoteine (3), (+)-6S-ocoteine N-oxide (4), and (+)-leucoxine (5). Third-stage larvae derived from the standard cross with wing cell markers mwh and/or flr(3) were treated chronically. The frequencies of mutant spots observed in marked heterozygous descendants revealed significant dose-dependent genotoxicity for alkaloids 1-4; compounds 1 and 2 were the most active. Alkaloids 1-4 also induced mitotic recombination. The presence of a methoxyl group at C-3 (as in compound 3) lowers its genotoxic effect relative to that of unsubstituted analogue 2, and the introduction of an N-oxide functionality (3 vs. 4) further reduces genotoxicity. The very planar conformation of oxo-aporphine alkaloid 1 may account for its higher genotoxicity vs. its less-planar analogues 3 and 4. As previously reported for (+)-dicentrine (2), alkaloids 1, 3, and 4 may also be DNA intercalating agents, interfering with the catalytic activity of topoisomerases.

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Section: Discussionsupporting

confidence: 86%

Mutagenicity and recombinagenicity of Ocotea acutifolia (Lauraceae) aporphinoid alkaloids

Guterres

Silva

Garcez

et al. 2013

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…In both cases, p53 can mediate cell cycle arrest, DNA repair, and/or apoptosis. We conclude that the results obtained by microarray hybridisations may point to dicentrine-induced DNA lesions, as already been found by others [19,32,41].…”

Section: Page 10 Of 23supporting

confidence: 86%

Inhibition of epidermal growth factor receptor over-expressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine

Konkimalla

Efferth

2010

Biochemical Pharmacology

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To cite this version:V. Badireenath Konkimalla, Thomas Efferth. Inhibition of epidermal growth factor receptor overexpressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine. Biochemical Pharmacology, Elsevier, 2010, 79 (8) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 23A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2 AbstractThe extraordinary relevance of EGFR in tumour biology makes it an exquisite molecular target for tumor therapy. Despite considerable success with these EGFR tyrosine kinase inhibitors in cancer therapy, resistance against these chemical compounds develops owing to the selection of point-mutated variants of EGFR. Therefore, there is an urgent need for the identification of novel EGFR tyrosine kinase inhibitors for treating tumours caused by such EGFR mutants. We found a preferential cytotoxicity of dicentrine towards U87MG.EGFR transduced with a constitutively deletion-activated EGFR expression vector as compared to non-transduced wild-type U87MG cells. As determined by microarray-based mRNA expression profiling, this preferential cytotoxicity was accompanied with an activation of BRCA1-mediated DNA damage response, p53 signalling, G1/S and G2/M cell cycle regulation, and aryl hydrocarbon receptor pathways. The activation of these signalling routes might be explained by the fact that dicentrine intercalates DNA and induces DNA strand break by inhibition of DNA topoisomerases. The cell cycle might be arrested by dicentrineinduced DNA lesions.

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“…It has been shown to induce frameshift mutations in Salmonella typhimurium TA1537 and this mutagenic action was attributed to its oxidation to mutagenic products (26). The clastogenic activity of apomorphine has been demonstrated in a Chinese hamster lung cell line in the absence of metabolic activation (S9 mix) (27).…”

Section: Mutagenicitymentioning

confidence: 99%

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Picada

Roesler

Henriques

2005

Braz J Med Biol Res

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Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/ microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites. Correspondence

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Clastogenicity of Aporphine Alkaloids in Vitro.

Cited by 15 publications

References 26 publications

Mutagenicity and recombinagenicity of Ocotea acutifolia (Lauraceae) aporphinoid alkaloids

Mutagenicity and recombinagenicity of Ocotea acutifolia (Lauraceae) aporphinoid alkaloids

Inhibition of epidermal growth factor receptor over-expressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

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