Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2013; 59(3): 50-57

Mechanisms of nephrotoxicity of novel anticancer compound maleimide derivative MI-1

Kharchuk IV, Andrukhova OO, Rybal'chenko VK, Andrukhov O

  1. Taras Shevchenko National University, Kyiv, Ukraine
  2. Vienna University of Animal Medicine, Austria
  3. Vienna Medical University, Austria
DOI: https://doi.org/10.15407/fz59.03.050


Abstract

The features of the impact of the maleimide derivative 1-(4-Cl-benzyl)-3-chloro-4-(CF3-fenilamino)-1H-pyrrole-2,5-dione (MI-1) on the viability and apoptosis-induced cell death of renal proximal and distal tubular epithelial cells and the amount of total and phosphorylated ERK1/2 were studied in order to establish possible mechanisms of nephrotoxicity induced by of MI-1. The viability and apoptosis of renal epithelial tubular cells after incubation with MI-1 were perfomed by 3,4,5-dymetyltiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT)-test and by flow cytometry after staining with specific antibodies to annexin V, respectively. The amount of ERK 1/2 was determined by Western blotting. The data indicate that MI-1 was more toxic with respect to the epithelial cells of distal than proximal tubule cells. The apoptosis-induced cell death pathway is involved in the mechanisms of MI-1 cytotoxicity. One of the possible mechanisms of MI-1 nephrotoxicity is increase in phosphorylation of ERK1/2 in the distal tubules. At the same time the increase amount of total ERK1/2 in proximal tubules under the influence of MI-1 may contribute to the survival of proximal tubular epithelial cells under the impact of a toxic factor or oxidative stress.

Keywords: Maleimide derivatives, nephrotoxicity, apoptosis, ERK1/2 signalling pathway

Full text: (PDF, in Ukrainian)

References

  1. Dubinina G.G., Golovach S.M., Kozlovs'kii V.O. Tolmachov A.O., Volovenko Yu.M. Antiproliferativna diya no-vih pohidnih 1-(4-R-benzil)-3-R1-4-(R2-fenilamino)-1H-pirol-2,5-dionu . Zhurn. organich. ta farmatsevt.himii. 2007. Vip. 5, N 1. P. 39-49.
    2.  
  2. Harchuk I.V. Vivchennya nefrotoksichnosti pohidnogomaleimidu 1-(4-Cl-benzil)-3-hlor-4-(CF3-fenilamino)-1N-pirol-2,5-dionu . Sovrem. probl. toksikologii.2009.N 2. P. 46-49.
    3.  
  3. Harchuk I.V., Karpezo N.O., Ostrovs'ka G.V., Ribal'chen-ko T.V., Ribal'chenko V.K. Osoblivosti morfo-funk-tsional'nogo stanu nirok pid vplivom riznih doz tatrivalosti dii potentsiinogo tsitostatika pohidnogomaleimidu 1-(4-Cl-benzil)-3-Cl-4-(CF3-fenilamino)-1N-pirol-2,5-dionu . Dop. NAN Ukraini. 2009,N 10. P. 185-188.
    4.  
  4. Harchuk I.V., Karpezo N.O., Filins'ka O.M., Yablons'kaLinchak O.V., Ribal'chenko V.K. Znizhennya nefro-toksichnogo vplivu oksidativnogo stresu pohidnimmaleimidu 1-(4-Cl-benzil)-3-Cl-4-(CF3-fenilamino)-1N-pirol-2,5-dionom . Urologiya. 2009. ? N 1. P. 27-31.
    5.  
  5. Yablons'ka S.V., Filins'ka O.M., Ostrovs'ka G.V.,Ribal'chenko V.K. Otsinka gepatotoksichnosti novogopohidnogo maleimidu z tsitostatichnoyu aktivnistyu iiogo vpliv na perekisne okislennya ta antioksidant-nu sistemu pechinki . Ukr. biohim. zhurn. 2009. 81,N 3. P. 83-92.
    6.  
  6. Arias J.L. Drug targeting strategies in cancer treatment:an overview . Mini Rev. Med. Chem. 2011. 11, N 1. P. 1-17. CrossRef PubMed
    7.  
  7. Burg M.B., Grantham J., Abramow M., Orloff J., SchaferJ.A. Preparation and study of fragments of single rabbitnephrons . J. Amer. Soc. Nephrol. 1997. 8, N 4 P. 675-683. PubMed
    8.  
  8. Fujita H., Omori S., Ishikura K., Hida M., Awazu M.ERK and p38 mediate highglucose-induced hypertrophyand TGF-beta expression in renal tubular cells . Amer. J.Physiol. Renal Physiol. ? 2004. 286, N 1. P. F120-F126. CrossRef PubMed
    9.  
  9. Jo S.K.; Cho W.Y.; Sung S.A.; Kim H.K, Won N.H. MEKinhibitor, U0126, attenuates cisplatin-induced renal injuryby decreasing inflammation and apoptosis . Kid. Int. 2005. 67, N 2. P. 458-466. CrossRef PubMed
    10.  
  10. Kharchuk I., Filinska O., Yablonska S., Rybalchenko V.Preventive action of maleimide derivative 1-(4-Cl-benzil)-3-Cl-4-(CF3-fenilamino)-1N-pyrrol-2,5-dion on rat's renalsystem in 1,2-dimethylhydrasine-induced colon carcinogenesis. Annales Universitatis Mariae Curie-Sklodowska.Lublin Polonia. Sectio DDD. Pharmacia. 2010. ? 23,N 2. P. 191-195.
    11.  
  11. Lynchak O., Ostrovska G., Rybalchenko V. Effects ofnew maleimide derivate on the 1,2-dimethylhydrazineinducedcolon carcinogenesis in rats . Gut «GASTRO2009 UEGW/WCOG, London». 2009. 58 (Suppl. II). P. A334.
    12.  
  12. di Mari J.F., Davis R., Safirstein R.L. MAPK activationdetermines renal epithelial cell survival during oxidativeinjury . Amer. J. Physiol. 1999. 277. P. F195-F203. PubMed
    13.  
  13. Mosmann T. Rapid colorimetric assay for cellular growthand survival: application to proliferation and cytotoxicityassays . J. Immunol. Meth. 1983. 65, N 1-2. P. 55-63.
    14.  
  14. Nowak G. Protein kinase C-alpha and ERK1/2 mediatemitochondrial dysfunction, decreases in active Na+transport, and cisplatin-induced apoptosis in renal cells. J. Biol. Chem. 2002. 277, N 45. P. 43377-43388. CrossRef PubMed PubMedCentral
    15.  
  15. Persons D.L., Yazlovitskaya E.M., Cui W., Pelling J.C. Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin . Clin. Cancer Research. 1999. 5. P. 1007-1014. PubMed
    16.  
  16. Qi W., Johnson D.W., Vesey D.A., Pollock C.A., Chen X. Isolation, propagation and characterization of primary tubule cell culture from human kidney . Nephrology (Carlton). ? 2007. 12. P. 155-159. CrossRef PubMed
    17.  
  17. Zhang J., Yang P.L., Gray N.S. Targeting cancer with small molecule kinase inhibitors . Nature Rev. Cancer. 2009. 9, N 11. P. 28-39. CrossRef PubMed
    18.  

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.