Cytotoxic activity of [Fe (μ ꢀSPh) (NO) ]
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 7, July, 2011
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cisplatin consists in the reduction of cellular glutathione
pool by NO donors. At the same time, it was noted
that the effect of NO on sensitivity of cells to chemical
agents depends on the type of cells and realizes by differꢀ
ent molecular mechanisms.26 We showed that the comꢀ
bined use of the Phꢀcomplex with cisplatin exhibits synerꢀ
gistic cytotoxic effects of these compounds (see Fig. 5).
This reflects the chemical sensitizating properties of the
Phꢀcomplex apparently related to its ability to spontaneꢀ
ously generate NO.
3. I. I. Lobysheva, M. V. Stupakova, V. D. Mikoyan, S. V.
Vasilieva, A. F. Vanin, FEBS Lett., 1999, 454, 177.
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Engl. Transl.), 2007].
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Konovalova, T. E. Sashenkova, S. M. Aldoshin, Ross. Khim.
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2009, 53].
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6, 434.
7
. T. Nguyen, D. Brunson, C. L. Crespi, B. W. Penman, J. S.
Nitric oxide affects the functions of the p53 tumor
suppressor. The p53 protein level in the cells is increased in
response to both administration of chemical NO doꢀ
Wishnok, S. R. Tannenbaum, Proc. Natl. Acad. Sci. USA,
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992, 89, 3030.
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. U. K. Messmer, B. Brune, Biochem. J., 1995, 319, 299.
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2
4,27
nors
and introduction into cells a gene which encodes
the enzyme NO synthase.2 It should be noted that activity
of p53 is required for the cell cycle arrest by the NO donor,
Nꢀ{4ꢀ[1ꢀ(3ꢀaminopropyl)ꢀ2ꢀhydroxyꢀ2ꢀnitrosohydrazino]ꢀ
butyl}ꢀ1,3ꢀpropanediamine, in the colorectal cancer cells
HCT 116, since in the p53ꢀdeficient HTC 116 cell line, no
cell cycle arrest in response to Nꢀ{4ꢀ[1ꢀ(3ꢀaminopropyl)ꢀ
8
1
1, 160.
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2
ꢀhydroxyꢀ2ꢀnitrohydrazino]butyl}ꢀ1,3ꢀpropanediamine
1
2. P. Chanvorachote, U. Nimmannit, C. Stehlik, L. Wang,
B.ꢀH. Jiang, B. Ongpipatanakul, Y. Rojanasakul, Cancer Res.,
2
7
is observed. Similar results were obtained for the RAW
64.7 macrophage cell line when treated with the NO
2
2
006, 66, 6353.
8
donor, Sꢀnitrosoglutathione. In our case, no dependence
of the cytotoxic effect on the activity of p53 was observed:
the HeLa cells containing the wildꢀtype p53 gene and the
H1299 cells which do not express p53 exhibit similar sensiꢀ
tivity to the Phꢀcomplex (see Figs 2 and 3).
1
3. P. Sonveaux, B. F. Jordan, B. Gallez, O. Feron, Eur. J.
Cancer, 2009, 45, 1352.
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Nauk, Ser. Khim., 2010, 1104 [Russ. Chem. Bull., Int. Ed.,
2
010, 59, 1126].
We found that the Phꢀcomplex causes an increase in
the amount of the p53 protein in the MCF7 cells (see Fig. 6),
that agrees with the literature data2 on the induction of
p53 in these cells exposed to the NO donors. In addition,
we discovered an effect of an increase in the apparent
molecular weight of the p53 protein by several kiloDalꢀ
tons. This phenomenon can be related to the covalent
modifications, since it is known that in process of activaꢀ
tion, the p53 protein undergoes phosphorylation and acetyꢀ
1
5. A. Weissberger, E. Proskauer, J. A. Riddick, E. E. Toops,
Organic Solvents: Physical Properties and Methods of Purificaꢀ
tion, Wiley, New York, 1955, 517.
7
1
1
6. T. C. Chou, P. Talalay, Advances in Enzyme Regulation, 1984,
2
2, 27.
7. O. H. Lowry, N. J. Rosenbrough, A. L. Farr, R. J. Randall,
J. Biol. Chem., 1951, 193, 265.
18. N. A. Sanina, G. V. Shilov, S. M. Aldoshin, A. F. Shestakov,
L. A. Syrtsova, N. S. Ovanesyan, E. S. Chudinova, N. I.
Shkondina, N. S. Emel´yanova, Izv. Akad. Nauk, Ser. Khim.,
lation.29 Similar change in the electrophoretic mobility
2
009, 560 [Russ. Chem. Bull., Int. Ed., 2009, 58, 572].
was observed for the amphibian p53 protein in response to the
DNAꢀdamaging factors, and, in this case, treatment with
phosphatase led to the decrease in the apparent molecular
1
2
2
9. S. H. Kaufmann, S. Desnoyers, Y. Ottaviano, N. E. Davidꢀ
son, G. G. Poirier, Cancer Res., 1993, 53, 3976.
0. P. M. Chumakov, Usp. Biol. Khim., 2007, 47, 3 [Biol. Chem.
Rev. (Engl. Transl.), 2007, 47].
1. W. R. Franek, Y. C. Chowdary, X. Lin, M. Hu, E. J. Miller,
J. A. Kazzaz, P. Razzano, J. Romashko III, J. M. Davis,
P. Narula, S. Horowitz, W. Scott, L. L. Mantell, J. Biol.
Chem., 2002, 277, 42694.
2. D. D. MaksimovicꢀIvanic, S. Mijatovic, L. Harhaji, D. Milꢀ
jkovic, D. Dabideen, K. F. Cheng, K. Mangano, G. Malꢀ
aponte, Y. AlꢀAbed, M. Libra, G. Garotta, F. Nicoletti,
S. StosicꢀGrujicic, Molecular Cancer Therapeutics, 2008,
30
30
weight of the protein. However, in the work no similar
changes in the human p53 protein were observed, and an
increase in the apparent molecular weight of p53 from
X.laevis affected only part of the cellular protein pool.
In our case, treatment of human MCF7 cells with the
Phꢀcomplex leads to entire transition of the p53 protein to
the form with the increased molecular weight. The nature
of the changes in properties of p53 treated with the
Phꢀcomplex remains unclear and requires additional studies.
2
2
7
, 510.
3. J. E. Saavedra, A. Srinivasan, G. S. Buzard, K. M. Davies,
D. J. Waterhouse, K. Inami, T. C. Wilde, M. L. Citro,
M. Cuellar, J. R. Deschamps, D. Parrish, P. J. Shami, V. J.
Findlay, D. M. Townsend, K. D. Tew, S. Singh, L. Jia, X. Ji,
L. K. Keefer, J. Med. Chem., 2006, 49, 1157.
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