In Response:

We appreciate the letter by Schönthal stating some interesting aspects of the role of prostaglandin pathways in the liver. The data obtained by Schönthal basically confirms our experimental findings (1). In his letter, Schönthal, however, disagrees with one of our conclusions, i.e., that the observed effects are caused to a significant extent by the cyclooxygenase-2 (COX-2)–inhibitory effect of celecoxib. Schönthal focused his analyses on cell viability and the detection of (down-regulated) Mcl-1 proteins by Western blot. We have shown that the effects of celecoxib lead to the activation of the intrinsic apoptosis pathway and have linked this to Mcl-1 (1). In addition, we have established that celecoxib-induced apoptosis is also, to a significant extent, mediated by activation of death receptor signaling pathways (1). This issue is not addressed by the data of Schönthal. We have shown that celecoxib increased the cell surface expression of different death receptors and, indeed, accumulating data provide evidence that death receptors are up-regulated in several hepatocellular carcinoma cells cell lines after treatment with other COX-2 inhibitors (2, 3). Thus, using down-regulation of Mcl-1 as the only molecular readout of the proapoptotic effects of COX-2 inhibitors is certainly not appropriate.

Schönthal claims that coxib concentrations of 0.1 to 1.0 μmol/L are sufficient to block prostaglandin E2 (PGE2) production (previously shown in a squamous cell carcinoma cell line) and that, therefore, concentrations of up to 100 μmol/L as used in our study would prove that the observed effects are PGE2-independent. In contrast, Wu et al. showed in cholangiocarcinoma cells that coxib concentrations of 40 μmol/L were necessary to inhibit PGE2 production by 74 % (4). Thus, the coxib concentration required to inhibit PGE2 production varies in different cancer cell lines.

Furthermore, Schönthal suggests that the drug effects of celecoxib are mimicked by other COX-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs. Indeed, we have previously shown that the same proapoptotic effects are generated by the use of meloxicam as well as with a slightly lower efficiency by the classic nonsteroidal anti-inflammatory drug sulindac (5). In addition, we have shown that reduced tumor cell viability induced by celecoxib is efficiently reverted by PGE2 supplementation (5).

Although it is certainly no central issue of our manuscript, evidence obtained by us and other groups shows a significant COX-2 dependency of the observed proapoptotic effects of celecoxib. Of course, additional COX-2–independent effects cannot be ruled out. Schönthal discusses important issues, but his data do not disprove that the observed effects are COX-2–dependent.

1
Kern MA, Haugg AM, Koch AF, et al. Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma.
Cancer Res
2006
;
66
:
7059
–66.
2
Yamanaka Y, Shiraki K, Inoue T, et al. COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced apoptosis.
Int J Mol Med
2006
;
18
:
41
–7.
3
Liu X, Yue P, Zhou Z, Khuri FR, Sun SY. Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells.
J Natl Cancer Inst
2004
;
96
:
1769
–80.
4
Wu GS, Zou SQ, Liu ZR, Tang ZH, Wang JH. Celecoxib inhibits proliferation and induces apoptosis via prostaglandin E2 pathway in human cholangiocarcinoma cell lines.
World J Gastroenterol
2003
;
9
:
1302
–6.
5
Kern MA, Schubert D, Sahi D, et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells.
Hepatology
2002
;
36
:
885
–94.