[Significance of cyclooxygenase-2 as a chemotherapeutic target in hepatocellular carcinoma].
OBJECTIVE
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence is dramatically increasing and no effective systemic treatments are available accentuating the urgent need for novel treatment approaches. A growing body of evidence suggest that COX-2 signaling is implicated in carcinogenesis and this study was conducted to evaluate the potential of selective COX-2 inhibition for the treatment and prevention of HCCs.


METHODS
The significance of COX-2 inhibition in HCCs was investigated in vitro (HCC cell-lines), in vivo (xenotransplanted tumors in nude mice) and ex vivo (precission-cut tissue sclice-cultures). Apoptosis-signaling was analyzed by means of immunohistochemistry, Western Blot analyses, Caspase-assays, FACS analyses after Nicoletti-staining, death receptor FACS-analysis, determination of mitochondrial membrane potential, and siRNA knockdown of Mcl-1.


RESULTS
Selective COX-2 inhibition led to a marked tumor-specific growth inhibition of human HCCs in vitro, in vivo and ex vivo based on reduction of proliferation and induction of apoptosis. Both, the death receptor (extrinsic)-, as well as the mitochondrial (intrinsic)-apoptotic pathways were involved. COX-2 inhibition led to an increased surface expression of death receptors and a marked down-regulation of Mcl-1, followed by translocation of Bax to mitochondria and a consecutive release of cytochrome c. Of clinical importance, COX-2 inhibition acted synergistically with chemotherapeutic drugs in the induction of apoptosis whereas primary human-hepatocytes were not sensitized towards apoptosis.


CONCLUSIONS
COX-2 inhibition offers therapeutic and preventive potential in HCC.
Kern
M A
MA
Pathologisches Institut, Universitäitsklinikum Heidelberg.
Schirmacher
P
P
Breinig
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000077239:Meloxicam; D051381:Rats; D013843:Thiazines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D013843:Thiazines; D013844:Thiazoles; D051546:Cyclooxygenase 2; D000077239:Meloxicam