Cyclooxygenase-2 inhibitors suppress the growth of human hepatocellular carcinoma implants in nude mice

Abstract

Cyclooxygenase (COX)-2 is expressed in hepatocellular carcinomas (HCCs) and HCC cell lines. COX-2 inhibition strongly suppresses growth of HCC cells in vitro by inducing apoptosis and reducing proliferation. Here, we evaluate the in vivo effects and mechanism of COX-2 inhibition of human HCC cell line derived xenotransplanted tumors in nude mice. Firstly, nude mice were treated with a COX-2 specific inhibitor (meloxicam) or a non-specific inhibitor (sulindac) starting 5 days prior to tumor cell injection. After 35 days mice were killed and tumors were analyzed morphologically and assayed for proliferation (Ki67), apoptosis (M30) and COX-2 expression. Secondly, mice were treated with meloxicam or sulindac after tumors had reached a diameter of at least 0.2 cm. COX-2 expression was maintained in implant tumors at levels comparable with parental cells. Selective COX-2 inhibition led to a significant reduction of tumor growth and weight. COX-2 inhibition had a significant anti-proliferative and pro-apoptotic effect on tumor cells. These results demonstrate that under experimental conditions selective COX-2 inhibition suppresses solid HCC growth in vivo and, therefore may have preventive and therapeutic potential for human HCCs.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Elevated COX-2 levels may be owing to IGF-II/IGF-1R-mediated induction of COX-2 expression as was already shown in colon carcinoma cells (Di Popolo et al, 2000). Vice versa, selective inhibition of COX-2 bioactivity by non-steroidal anti-inflammatory drugs (NSAIDs; for example, celecoxib) leads to reduced IGF-1R expression in HCC cells (unpublished own data), which may in part explain the observed proapoptotic effects of celecoxib on these cells (Kern et al, 2002(Kern et al, , 2004.…”

Radiosensitizing potential of the selective cyclooygenase-2 (COX-2) inhibitor meloxicam on human glioma cells

“…arthritis). The anti-tumor effect of selective COX-2 inhibitors, reported both in vitro and in vivo experimental studies [10][11][12], supported the introduction of these compounds in the clinic. However, the mechanism of action of these inhibitors is not well understood.…”

“…The COX-2 inhibitor meloxicam was reported to inhibit growth of various tumor cell types both in vitro and in vivo [10,12,22,23,29,30]. Until now, neither the growth inhibitory capacity nor the radiosensitizing potential of meloxicam was tested on human glioma cells.…”

“…Interestingly, selective COX-2 inhibitors also demonstrated to act as a radiosensitizer [5,[15][16][17][18][19][20][21]. The selective COX-2 inhibitor meloxicam has been shown to inhibit cell proliferation of different cancer cell lines and animal tumors [10,12,[22][23][24][25]. However, no data are available yet on glioma cells.…”

Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice

“…(12,13) Selective COX-2 inhibitors have been regarded as a new group of anticancer drugs based on the observation that expression of COX-2 is elevated in a variety of human cancers (14)(15)(16)(17)(18) including HCC, (19,20) and COX-2 has been shown to promote growth and inhibit apoptosis of cancer cells. (21) A number of studies have investigated the use of meloxicam, a selective COX-2 inhibitor, in inhibiting growth of cancers of ovarian, (22) bladder, (23) biliary duct, (24) breast, (25) lung, (26) and colon. (27) Meloxicam has also shown anticancer activity to treat HCC in vitro and in vivo.…”