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The effect of the anticancer drug doxorubicin on cytomegalovirus-infected human fibroblasts

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Abstract

The anticancer antibiotic doxorubicin (DOX) is highly toxic and has life-threatening side effects. The effect of DOX on normal cells is not well studied. It has been proposed that DOX induces cancer cell death by apoptosis. However, information regarding the role of p73 protein, a member of the p53 tumor suppressor family, is sparse. Cytomegalovirus (CMV) triggers an antiapoptotic program, and the virus is able to carry out genome replication before the death of the target cell. Our goal was to examine the effect of DOX on normal cells, analyze the ability of the CMV-induced antiapoptotic program to reduce DOX toxicity, and examine the involvement of p73 protein and its isoforms in the regulation of death of CMV-infected and DOX-treated cells. Cell counting revealed that DOX killed about 70% of human embryonic lung fibroblasts (HELFs) in culture. Combined exposure to DOX and CMV reduced cell death. The cell number with DNA breaks found by TUNEL declined from 5.2 to 3.2% (p < 0.05) after DOX exposure of CMV-infected cells. Analysis of mitotic figures revealed that DOX caused accumulation of mitotic cells, which was not observed in CMV-infected and DOX-treated cells. PCR analysis of mRNA of two p73 protein isoforms (TAp73 and dNp73) showed that, in uninfected cells, TAp73 isoform expression was low, while in CMV-infected cells the level of TAp73 was significantly higher and for the first time dNp73 expression was registered. Infected cells treated with DOX did not exhibit mitosis block. The cells displayed activation of caspases 8, 9, and 3 accompanied by the cells’ death; however, this was not as large-scale as in cultures exposed only to DOX. From these findings, it can be concluded that CMV reduces DOX-related damage in normal cells. This suggests that TAp73 and dNp73 induction provides conditions that diminish DOX-produced DNA damage and death of normal cells.

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Abbreviations

DOX:

doxorubicin

CMV:

cytomegalovirus

HELF:

human embryonic lung fibroblasts

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Authors and Affiliations

  1. Ivanovsky Institute of Virology, Ministry of Health of the Russian Federation, Moscow, 123098, Russia

    N. E. Fedorova, E. V. Chichev, A. V. Murzakova, A. A. Kirichenko & A. A. Kushch

  2. Russian Research Centre Kurchatov Institute, Konstantinov Petersburg Nuclear Physics Institute, St. Peterburg, 188300, Russia

    S. S. Emelianova, G. R. Vinogradskaya & V. N. Verbenko

  3. St. Petersburg State Polytechnical University, St. Petersburg, 195251, Russia

    G. R. Vinogradskaya

Authors
  1. N. E. Fedorova
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  2. S. S. Emelianova
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  3. G. R. Vinogradskaya
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  4. E. V. Chichev
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  5. A. V. Murzakova
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  6. A. A. Kirichenko
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  7. V. N. Verbenko
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  8. A. A. Kushch
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Corresponding author

Correspondence to G. R. Vinogradskaya.

Additional information

Original Russian Text © N.E. Fedorova, S.S. Emelianova, G.R. Vinogradskaya, E.V. Chichev, A.V. Murzakova, A.A. Kirichenko, V.N. Verbenko, A.A. Kushch, 2015, published in Tsitologiya, 2015, Vol. 57, No. 4, pp. 260–268.

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Fedorova, N.E., Emelianova, S.S., Vinogradskaya, G.R. et al. The effect of the anticancer drug doxorubicin on cytomegalovirus-infected human fibroblasts. Cell Tiss. Biol. 9, 377–384 (2015). https://doi.org/10.1134/S1990519X15050053

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  • DOI: https://doi.org/10.1134/S1990519X15050053

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