Hepatocellular carcinoma (HCC) is one of deadliest cancers worldwide and ranking the third among all cancer-related mortalities. Current effective therapeutic approaches for HCC include surgical resection and trans-arterial embolization (TAE). Chemotherapy remains largely ineffective, and most popular used agents are epirubicin, doxorubicin, cisplatin and 5-FU. Besides, these chemotherapic drugs had potential serious side-effects such as low blood count, hair loss, vomiting, and they rarely present good anti-HCC effect in clinical practice. Our previous studies found that epirubicin injection attenuated the tumor burden of orthotopic Novikoff hepatoma, but caused serious side effects to hosts including reduction in spleen weight, white count, and body weight and high GOT level. Therefore, we aimed to evaluate possible alternative treatment such as COX-2 inhibitor for HCC. Celecoxib is a highly selective COX-2 inhibitor and less toxic than the traditional non-selective NSAIDs. Celecoxib showed relatively low cytotoxicity in Novikoff N1-S1 hepatoma cells and Clone 9 normal hepatocytes with an IC50 of up to 100 microM. Expression analysis revealed that COX-2 expression is very low in N1-S1 cells at protein and mRNA levels. Thus, N1-S1 is a kind of hepatoma cell line with low COX-II level. Interestingly, celecoxib upregulated PTEN expression and decreased AKT phosphorylation in vitro by COX-2 independent pathway, and then oral administration of celecoxib (30 mg/kg) for 7 days showed tendency of tumor suppression of Novikoff hepatoma in rats revealed by ultrasound and computed tomography (CT) scan. Histological analysis revealed that CD31-positive neo-vascularization¡BKi-67-positive cell-proliferation and FOXP3-positive regulatory T cells were found to reduce in celecoxib-treated rats, and then TUNEL-positive apoptotic cells were found to increase in celecoxib-treated rats. Besides, celecoxib-treated rats exhibited no significant side effect. Therefore, oral celecoxib may be a suitable chose of adjuvant therapy in combination with epirubicin or other chemotherapeutic agents for the treatment of HCC.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0826109-163159 |
| Date | 26 August 2009 |
| Creators | Chu, Tian-huei |
| Contributors | Tsung-Hui Hu, Jiin-Tsuey Cheng, Ming-Hong Tai |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0826109-163159 |
| Rights | not_available, Copyright information available at source archive |
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