Abstract
We previously reported that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, suppresses growth of human hepatocellular carcinoma (HCC) cells through both COX-2 dependence and independence. Recently, we established COX-2-deleted human HCC cells, C2D-HuH7, and C2D-HuH7-bearing nude mice. Using this novel model, we examined the pharmacological effects and mechanisms of celecoxib on in-vivo growth of HCC xenografts in relation to COX-2 expression. After treatment with celecoxib, the mice bearing HuH7 or C2D-HuH7 xenografts were assessed for the pharmacological effects and mechanisms of celecoxib on HCC xenog raft growth in relation to COX-2 expression. Celecoxib resulted in an effective and comparable growth reduction of both COX-2-expressing and COX-2-deleted HuH7 xenografts in association with decreased Ki-67 expression. These results demonstrated celecoxib's COX-2-independent in-vivo anti-HCC effects. Celecoxib increased peroxisome proliferator-activated receptor γ predominantly in HuH7 xenografts, indicating its COX-2 dependency. Celecoxib reduced p-Rb and DP1/E2F1 complex predominantly via upregulated p21 /CDK4 complex in HuH7 xenograft, but p27/CDK4 complex in C2D-HuH7 xenografts. The effects of celecoxib on phosphatase and tensin homolog deleted on chromosome ten/PI3K/Akt signaling were COX-2 independent, but its effects on extracellular-regulated kinase signaling seemed COX-2 dependent. In addition, the effects of celecoxib on AC-H3, AC-H4, and histone deacetylase 2 could be both COX-2 dependent and independent. In conclusion, celecoxib suppresses growth of HuH7 xenografts regardless of COX-2 expression, which may be mediated through different signaling.
Original language | English (US) |
---|---|
Pages (from-to) | 891-897 |
Number of pages | 7 |
Journal | Anti-cancer drugs |
Volume | 19 |
Issue number | 9 |
DOIs | |
State | Published - Oct 2008 |
Externally published | Yes |
Keywords
- Cell cycle
- Cyclooxygenase-2
- Cyclooxygenase-2 deletion
- Cyclooxygenase-2 inhibitor
- Hepatocellular carcinoma
ASJC Scopus subject areas
- Oncology
- Pharmacology
- Pharmacology (medical)
- Cancer Research