Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts.
Cell cycle progression in eukaryotic cells is regulated by a family of cyclin-dependent kinases (CDKs). Cyclin E is a regulatory subunit of CDK2 and drives cells from G1 to S phase. Increased expression of cyclin E is a frequent event in human malignancies and has been associated with poor prognosis in various cancers. In this study, we evaluated the effects of cyclin E-overexpression on the sensitivity of rat fibroblasts to anticancer drugs. Cyclin E-overexpressing cells were less sensitive to doxorubicin-induced inhibition of cell growth but not to other antineoplastic drugs, such as paclitaxel, vincristine, etoposide and methotrexate. Cyclin E-overexpressing fibroblasts also displayed a reduction in ROS levels and a significantly lower increase following doxorubicin treatment compared with vector control cells. The expression of manganese superoxide dismutase (MnSOD) and its activity were increased (about 1.3-fold) in cyclin E-overexpressing derivatives compared with control cells. These results suggest that cyclin E overexpression might reduce tumour cells sensitivity to doxorubicin by affecting the expression of MnSOD and that determination of cyclin E expression levels might help to select patients to be treated with an anthracycline-based antineoplastic therapy.
Sgambato
A
A
Istituto di Patologia Generale, Centro di Ricerche Oncologiche 'Giovanni XXIII', Catholic University, Largo Francesco Vito 1, 00168 Rome, Italy. asgambato@rm.unicatt.it
Camerini
A
A
Pani
G
G
Cangiano
R
R
Faraglia
B
B
Bianchino
G
G
De Bari
B
B
Galeotti
T
T
Cittadini
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D002478:Cells, Cultured; D019927:Cyclin E / Q000096:biosynthesis*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis
D000970:Antineoplastic Agents; D019927:Cyclin E; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D013482:Superoxide Dismutase