Celecoxib May Fight Liver Cancer

Fran Lowry

May 24, 2011

May 24, 2011 — The cyclooxygenase 2 (COX-2) inhibitor celecoxib, which has shown anticancer effects in malignancies of the colon, lung, and prostate, may also be a candidate for the treatment of liver cancer, according to new research published online April 13 in Cancer Prevention Research.

Scientists, led by Yan Liu, PhD, from Ohio State University in Columbus, report that celecoxib may have anticancer activity because it blocks the interleukin 6/signal transducer and activator of transcription 3 (STAT3) pathway and causes apoptosis in liver cancer cells.

They made their discovery in human hepatocellular carcinoma (HCC) cells.

Jiayuh Lin, PhD, an associate professor of paediatrics at Ohio State and senior author of the study, told Medscape Medical News he would advocate taking a COX-2 inhibitor as a preventive measure.

Dr. Jiayuh Lin

"Based on the ability of celecoxib to inhibit both STAT3 and COX-2, it may have some beneficial effects in cancer prevention," he said.

Dr. Lin explained that there is growing evidence demonstrating an association between chronic liver inflammation and HCC development. STAT3, which is associated with inflammation and cellular transformation, is activated in human HCC tissue but not in normal human liver tissues.

The researchers found that celecoxib decreased STAT3 phosphorylation to cause the liver cancer cells to self-destruct. They also found that celecoxib blocked exogenous interleukin-6–induced STAT3 phosphorylation and nuclear translocation.

Importantly, they also observed that when celecoxib was combined with doxorubicin or sorafenib, more HCC cells in culture were killed.

"Each chemotherapy drug alone will reduce the growth of cancer cells, but when each drug was combined with celecoxib, a greater growth suppression effect was observed," Dr. Lin said. "Therefore, we believe that celecoxib can be combined with other anticancer drugs to reduce drug resistance caused by interleukin-6 STAT3 signals."

This research adds to the growing evidence for a possible role for COX-2 inhibition in various cancers.

Cardiovascular Concerns

However, cardiovascular concerns have long been an issue with this class of drugs.

In a study that was presented at the 2008 Annual Meeting of the American Association for Cancer Research, Monica Bertagnolli, MD, from Brigham and Women's Hospital in Boston, Massachusetts, reported that celecoxib reduced the 5-year rate of advanced colorectal adenomas by 41% in high-risk patients who took the drug for 3 years.

However, subjects had to discontinue taking the drug as concerns about cardiovascular safety began to emerge.

Nevertheless, the protection from adenomas continued after use of the drug was stopped, and Dr. Bertagnolli concluded that COX-2 inhibitors are promising in patients who are at risk of developing adenomas and who do not have cardiovascular risk factors.

In another study that was presented the same year at the Annual Meeting of the American Society of Clinical Oncology, Edward Kim, MD, from the M.D. Anderson Cancer Center in Houston, Texas, reported that celecoxib was able to reduce the expression of Ki-67, a biomarker associated with bronchial premalignant lesions, and could have a chemoprotective effect against lung cancer.

The study, which was conducted in current or former smokers with at least a 20 pack-year smoking history, was also halted because of fears of cardiovascular toxic effects but resumed after advisers to the US Food and Drug Administration recommended that it be continued.

Medscape Medical News invited Craig A. Elmets, MD, professor and chair, Department of Dermatology, University of Alabama at Birmingham, to comment on the use of COX-2 inhibitors for chemoprevention.

"I think we can add hepatocellular carcinoma to the potential types of cancer which will respond to NSAIDs [nonsteroidal anti-inflammatory drugs]," he said.

Dr. Elmets recently headed a multicenter randomized controlled trial that found that celecoxib may be effective for prevention of squamous cell carcinomas and basal cell carcinomas in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

"We treated patients with nonmelanoma skin cancers for 9 months, and in the patients who received celecoxib there was a greater than 50% reduction in the number of new nonmelanoma skin cancers that developed compared to a control group that didn't receive celecoxib," he said in an interview.

Dr. Elemets said that when his study was started, concerns about the cardiovascular adverse effects with celecoxib had not yet surfaced. Similar to the other trials, his was stopped when these concerns came to light. However, during the 9 months that patients took celecoxib no increase in cardiovascular risk was seen, he noted.

Possible Alternatives to Celecoxib

Dr. Elmets admitted that if the COX-2 inhibitors are going to be taken to prevent cancer, then the cardiovascular risk they pose could become an issue.

"People need to be on these drugs on a chronic basis for preventive benefit," he explained. "Celecoxib blocks the cyclooxygenase 2 enzyme, but there are a number of other drugs that also block COX-2 that have much less of a cardiovascular risk, so these may be ideal for prevention of various types of cancers."

Sulindac (Clinoril, Merck) is one, he said. "Combined with difluoromethylornithine, it produces a dramatic reduction in the number of colorectal adenomas, so I think that there is definitely something going on here with regard to chemoprevention."

A COX-2 inhibitor may be particularly useful in hepatitis B–positive patients who are at risk for HCC.

"Hepatocellular carcinoma is not a common malignancy in the US, but in patients who are hepatitis B positive, this may be a drug that should be considered because mortality rate for hepatocellular carcinoma is really quite high," he said.

"Naproxen has much less of a cardiovascular effect than the other NSAIDs, so there would be quite a bit of interest in looking at naproxen," he added.

Using lower NSAID doses or screening people for cardiovascular risk factors may be other strategies that will enable these drugs to be used as effective chemopreventive agents. "So might using these drugs intermittently or using them in combination with other drugs at much lower doses than are normally used," Dr. Elmets said.

Dr. Li, Dr. Lin, and Dr. Elmets have disclosed no relevant financial relationships.

Cancer Prev Res. Published online April 13, 2011 Text

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