EFFECT OF ANTI-CANCER DRUG DOXORUBICINE ON CYTOMEGALOVIRUS
INFECTED HUMAN FIBROBLASTS
N.E. Fedorova,1 S.S. Emelianova,2 G.R. Vinogradskaya,2,3,* E.V. Chichev,1 A.V. Murzakova,1
A.A. Kirichenko,1 V.N. Verbenko,2 A.A. Kushch 1
1 D.I. Ivanovsky Institute of Virology, Ministry of Health of Russian Federation, Moscow,
2 B.P. Konstantinov Petersburg Nuclear Physics Institute, NRC «Kurchatov Institute», St. Petersburg,
and 3 St. Petersburg State Polytechnical University;
* e-mail: vandasedova@rambler.ru
The anticancer antibiotic doxorubicine (DOX) is highly toxic and induces functional complications in
vital organs. The effect of DOX on normal cells has not been examined in sufficient detail, and the search for
compounds reducing DOX toxicity did not lead to success so far. It has been suggested that DOX induces death
of cancer cells via p53-dependent apoptosis, however, the information regarding the role of ð73 protein, a member
of ð53 tumor suppressor family, is scanty. Cytomegalovirus (CMV) induces an antiapoptosis program that
allows its replication until death of the target cell. Our objectives were to examine the effect of DOX on normal
cells (human fibroblasts), analyze the ability of CMV-induced antiapoptosis program to reduce DOX toxicity,
and to evaluate the involvement of ð73 protein and its isoforms in the regulation of death of CMV-infected and
DOX-treated cells. Within a 24-h time period DOX caused death of about 70 % human embryonic lung fibroblasts
(HELF) in cell culture, this parameter decreased significantly in CMV-infected DOX-treated HELF cells.
TUNEL has shown that the number of cells with DNA fragmentation decreases from 5.2 % under the effect of
DOX to 3.2 % (P < 0.05) after combined CMV-DOX treatment. Analysis of mitotic figures revealed that DOX
causes accumulation of mitotic cells, which was not observed in CMV-infected DOX-treated cells. PCR analysis
of mRNA of two ð73 protein isoforms (ÒÀð73 and dNp73) has shown that in uninfected cells the expression
of ÒÀð73 isoform was low, while in CMV-infected cells level of TAp73 was significant and expression of
dNð73 was demonstrated for the first time. Expression of TAp73 associated with lack of mitosis block. The activation
of caspases 8, 9 and 3 in CMV-infected cells was registered but cell death was not, however, as massive
as that caused by DOX. From these findings it can be concluded that CMV attenuates DOX-related damage to
normal cells. It can be suggested that induction of TAp73 and dNp73 isoforms provides conditions for reduction
of DOX effect which leads to DNA damage and death of normal cells.
Key words:
doxorubicin, fibroblasts, cytomegalovirus, ÒÀð73, dNp73, ð73
| Back
| Contents
| Main |
|
