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Administration of isothiocyanate-derived mercapturic acids inhibits solid tumor growth of 4T1 murine mammary carcinoma cells in BALB/c mice

Mateusz Psurski 1,2Beata Filip-Psurska 2Joanna Wietrzyk 2Józef Oleksyszyn 1

1. Wroclaw University of Technology, Division of Medicinal Chemistry and Microbiology (PWR), Wybrzeże Wyspiańskiego 27, Wrocław 50-370, Poland
2. Polish Academy of Sciences, Institute of Immunology and Experimental Therapy (IITD), Rudolfa Weigla 12, Wrocław 53-114, Poland


Background. Mercapturic acids are a metabolites of naturally occurring isothiocyanates – well-known constituents present in cruciferous vegetables exhibiting high anticancer activity in vivo. Isothiocyanates enter the cells via passive diffusion and are rapidly conjugated with glutathione, main intracellular thiol acting as a redox guardian. Next, they undergo a successive rearrangements - mercapturic acid pathway, which ends when dithiocarbamate (mercapturic acid) is excreted outside the cell. There, it can undergo slow hydrolysis resulting in isothiocyanate’s moiety release which can re-enter the cell. Due to these metabolic cycle, mercapturic acids can be treated as isothiocyanate’s intracellular reservoir. Moreover, recent findings indicates that they can directly modulate cancer cells metabolism, growth and proliferation acting as histone deacetylase inhibitors. Application of the isothiocyanates as an inhibitors of tumor growth in vivo in difficult, because of their pungent taste and smell, low water solubility and potential stomach irritating effect. Mercapturic acids lack these adverse effect, thus, they application in vivo should be possible.

Aim of the study. The comparison of mercapturic acids and their parental isothiocyanates activity in vivo.

Methods. A series of mercapturic acids were synthesized from parental isothiocyanates using well established methods. Balb/c, female mice were inoculated with 4T1 cancer cells grown in vitro. Tested compounds were administered 5-times a week (300umol/kg b.w., i.p.), tumor growth and body weight change was evaluated 3-times a week. In the 31th day of the experiment animals were sacrificed, organs were weight, blood was collected for further morphological and biochemical analysis.

Results. All five isothiocyanate-derived mercapturic acids (benzyl (NAC-1), phenethyl (NAC-2), allyl (NAC-3), 3,4-dimetoxybenzyl (NAC-4), 6-benzyloxyhezyl (NAC-5)) showed anticancer activity. The highest activity was observed for NAC-4 and NAC-5 (49% and 40% of tumor growth inhibition (TGI), respectively), the lowest for NAC-3 (17% TGI). No significant differences between the activity of mercapturic acid and the corresponding isothiocyanate was observed. However, mercapturic acid had less pronounce influence on body weight change than corresponding isothiocyanate (e.g. 9.5% and 1.9% of body weight decrease (BWD) for ITC-1 and NAC-1, respectively), thus, they might be safer as anticancer drugs in further applications. Morphological blood analysis showed increased level of erythrocytes, hepatocyte and hemoglobin in all groups treated with isothiocyanates/mercapturic acids. Interestingly, leucocytes level was positively correlated with anticancer activity (the highest level was achieved for NAC-4), indicating their possible immunostimulating activity. Analysis of LDH, ALTL, ASTL enzymes, as well as creatinine, urea, albumin and bilirubin showed no significant differences, however level of albumin and bilirubin was decreased in groups treated with tested compounds.   

Conclusions. Isothiocyanates and the corresponding mercapturic acids showed comparable acticancer activity against 4T1 murine mammary gland tumor. Significant tumor growth inhibition was observed especially for NAC-4, NAC-5 and the corresponding isothiocyanates. All results obtained during the present studies indicates that isothiocyanates might be replaced by mercapturic acids in further in vivo studies.

This work was supported by a grant of National Science Centre, grant no. 2011/01/N/NZ4/03361.


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Presentation: Poster at IX Multidyscyplinarna Konferencja Nauki o Leku, by Mateusz Psurski
See On-line Journal of IX Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2014-03-17 22:38
Revised:   2014-05-02 17:35