Painkillers vs. cancer

Specifically, they found that celecoxib (used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis) slows the growth rate of a specific kind of cancer in animal models. This suggests that the medication—currently marketed by Pfizer under the brand name Celebrex primarily but also as Celebra and Onsenal—could have the same effect on other types of tumors.

Celebrex targets an enzyme called cyclooxygenase-2 (COX-2), which is linked to pain and inflammation. This enzyme is also critical in the creation of prostaglandins, compounds that act like hormones and play a role in promoting tumor growth, the TSRI researchers note. COX-2 expression is typically low in normal tissue, but high in multiple types of cancers.

“We were actually interested in determining what a particular signaling pathway does in cancer,” said Joseph Kissil, a TSRI associate professor who led the study. “In the process, we found that it activates genes that promote survival of tumor cells and that they do so by turning on enzymes involved in inflammation, including COX-2, which anti-inflammatory drugs like Celebrex inhibit.”

From there the researchers progressed to conduct animal studies designed to track the effects of celecoxib on the growth of cancer cells from a tumor type known as neurofibromatosis type II (NF2). In humans, NF2 is a relatively rare inherited form of cancer caused by mutations in the antitumor gene NF2, which leads to benign tumors of the auditory nerve. Those animal models showed a significantly slower tumor growth rate in celecoxib-treated models than in controls.

The TSRI study also indicated that a signaling cascade known as the Hippo-YAP pathway is involved in these results and that the protein YAP is required for the proliferation and survival of NF2 cells and tumor formation.

“Our study shows that COX-2 inhibitors do have an effect on the tumor cells,” said William Guerrant, a TSRI research associate and the first author of the study. “They also have an impact on inflammatory responses that play a role in tumor growth. It’s possible that in other cancers these effects might actually be stronger because of the drug’s impact on inflammation.”

Surprisingly enough, that isn’t the first commonly prescribed painkiller to demonstrate a link to potential cancer treatment this year, nor the first COX-2 inhibitor to do so.

Back in January, the Repurposing Drugs in Oncology (ReDO) Project published a clinical study suggesting that diclofenac—sold under the brand names Voltaren, Zipsor, Pennsaid, Solaraze, Cambia, Flector, Cataflam and Dyloject and used for migraines, rheumatoid arthritis, fever, gout and postoperative pain—has cancer-fighting properties.

As the abstract for the ReDO paper notes: “Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting.”

The abstract further notes that diclofenac, which is “a potent inhibitor of COX-2 and prostaglandin E2 synthesis,” displays a range of effects on the immune system, the angiogenic cascade, chemosensitivity, radiosensitivity and tumor metabolism in both preclinical and clinical models. “Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents,” the abstract concludes.

“It's still somewhat surprising that there is still so much we don't understand about how many of the standard drugs we use every day, like diclofenac, work,” noted study author Pan Pantziarka, a member of the ReDO project, in a news release about the study. “But the more we learn, the more we can see that these drugs are multitargeted agents with interesting and useful effects on multiple pathways of interest in oncology.”

Pantziarka and colleagues noted in the news release that previous studies have shown that the drug could reduce tumor size in fibrosarcoma, colorectal cancer, neuroblastoma, ovarian cancer and several other cancers.