Seliciclib (CYC202, R-roscovitine) enhances the antitumor effect of doxorubicin in vivo in a breast cancer xenograft model.
We sought to determine whether seliciclib (CYC202, R-roscovitine) could increase the antitumor effects of doxorubicin, with no increase in toxicity, in an MCF7 breast cancer xenograft model. The efficacy of seliciclib combined with doxorubicin was compared with single agent doxorubicin or seliciclib administered to MCF7 cells and to nude mice bearing established MCF7 xenografts. Post-treatment cells and tumors were examined by cell cycle analysis, immunohistochemistry and real-time PCR. Seliciclib significantly enhanced the antitumor effect of doxorubicin without additional murine toxicity. MIB1 (ki67) immunohistochemistry demonstrated reduced proliferation with treatment. The levels of p21 and p27 increased after treatment with doxorubicin or seliciclib alone or in combination, compared to untreated controls. However, no changes in p53 protein (DO1, CM1), survivin or p53 phosphorylation (SER15) were observed in treated tumors compared with controls. In conclusion, the CDK inhibitor seliciclib (R-roscovitine) enhances the antitumor effect of doxorubicin in MCF7 tumors without increased toxicity with a mechanism that involves cell cycle arrest rather than apoptosis.
Appleyard
Maria Virginia C L
MV
Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom. m.v.c.l.appleyard@dundee.ac.uk
O'Neill
Mary A
MA
Murray
Karen E
KE
Paulin
Fiona E M
FE
Bray
Susan E
SE
Kernohan
Neil M
NM
Levison
David A
DA
Lane
David P
DP
Thompson
Alastair M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage*; D000077546:Roscovitine
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D018844:Cyclin-Dependent Kinases