A synthetic uracil derivative with antitumor activity through decreasing cyclin D1 and Cdk1, and increasing p21 and p27 in MCF-7 cells.
The anticarcinogenic potential of (RS)-1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)uracil (DBDU), with the naturally occurring pyrimidine base uracil, is reported against the MCF-7 cancer cell line. The arrest in the G0/G1 and G2/M cell cycle phases was accounted for by decrease in the expression of the cyclin D1 and Cdk1 proteins, and increase in p21 and p27 proteins. Using a reverse transcription-polymerase chain reaction-based assay at a dose of 5 muM of DBDU cyclin D1 mRNA was decreased, suggesting that DBDU exerts its regulatory action on cyclin D1 at the level of transcription. DNA fragmentation was performed and demonstrated that apoptosis occurred in the tumor cell line treated with DBDU. The G0/G1 arrest is an irreversible process and the cells undergo apoptosis in a p53-independent manner. DBDU administered intravenously twice a week (50 mg/kg dose each time) induced neither toxicity nor death in mice for 5 weeks.
Marchal
Juan A
JA
Departamento de Ciencias de la Salud, Facultad de Ciencias Experimentales y de la Salud, Paraje de las Lagunillas s/n, 23071 , Jaen, Spain.
Núñez
María C
MC
Suárez
Inés
I
Díaz-Gavilán
Mónica
M
Gómez-Vidal
José A
JA
Boulaiz
Houria
H
Rodríguez-Serrano
Fernando
F
Gallo
Miguel A
MA
Espinosa
Antonio
A
Aránega
Antonia
A
Campos
Joaquín M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D015415:Biomarkers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014498:Uracil; D016203:CDC2 Protein Kinase