Sensitivity to the non-COX inhibiting celecoxib derivative, OSU03012, is p21(WAF1/CIP1) dependent.
OSU03012 is a non-COX inhibiting celecoxib derivative with growth inhibiting and apoptotic activity in many cancer cell lines. To investigate mechanisms related to cell cycle proteins in growth inhibition and apoptosis induced by OSU03012, the primary human oral epithelial cell line, TE1177, was transformed with HPV16 E6 (TE/E6), HPV16 E7 (TE/E7) or empty vector (TE/V). TE/E6 cell lines exhibiting low levels of p53 and undetectable levels of p21(WAF1/CIP1) were sensitized to the growth inhibiting and apoptotic effects of OSU03012. The TE/E7 cell lines expressing low levels of Rb and elevated levels of p53 and p21(WAF1/CIP1) were resistant. OSU03012 reduced the number of cells in the S phase of the TE/E7 and TE/V cell lines with intact p53-p21(WAF1/CIP1) checkpoint, but not in the checkpoint defective TE/E6 cell lines. Treatment with OSU03012 also markedly reduced the levels of cyclin A and Cdk2 in TE/E7 and TE/V, but not in TE/E6 cell lines, which had significantly enhanced basal levels of cyclin A and Cdk2. Consistent with the TE/E6 cell line, p21(WAF1/CIP1)-/- mouse embryo fibroblasts were more sensitive to OSU03012-induced apoptosis as evidenced by PARP and caspase 3 cleavages. These data suggest that p21(WAF1/CIP1) is an important factor in the sensitivity of cells to the growth inhibiting and apoptotic effects of OSU03012.
Ding
Haiming
H
Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. ding.29@osu.edu
Han
Chunhua
C
Guo
Dongmei
D
Wang
Dasheng
D
Duan
Wenrui
W
Chen
Ching-Shih
CS
D'Ambrosio
Steven M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002460:Cell Line; D019925:Cyclin A / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000378:metabolism; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D012097:Repressor Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014412:Tumor Virus Infections / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; C068651:E6 protein, Human papillomavirus type 16; C500894:OSU 03012; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D012097:Repressor Proteins; D013449:Sulfonamides; C059731:oncogene protein E7, Human papillomavirus type 16; D001973:Bromodeoxyuridine
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