Celebrex, a drug currently marketed for its anti-inflammatory properties, may have anti-tumor and cancer prevention effects, particularly because it blocks STAT3 signaling, suggests new research.
Celecoxib, known to consumers as Celebrex, is a COX-2 inhibitor, which selectively blocks an enzyme responsible for inflammation and pain, COX-2. Celecoxib has recently been gaining credit for its anti-tumor effects as well. Investigators at Nationwide Children’s and The Ohio State University suspect that its anti-tumor powers are tied, in part, to the drug’s ability to bind to STAT3.
STAT3 is a member of a protein family that plays a role in relaying signals from cytokines and growth factors. The abnormal activation of STAT3 protein is becoming more commonly associated with unrestricted cell growth and transformation of normal cells into malignant cells. Abnormal STAT3 activation has been frequently seen in human cancer cell lines and tumor samples from patients and shows cancer-causing-capabilities in cultured cells and mouse tumor models.
Using a multiple-fragment simultaneous computer binding model and drug repositioning, Dr. Chenglong Li at the Ohio State University College of Pharmacy found that celecoxib binds to STAT3 and prevents it from activating. Armed with this computer modeling evidence, the team at Nationwide Children’s and The Ohio State University conducted laboratory-based studies to determine whether celecoxib does in fact inhibit activation of STAT3 in human cancer cells and in turn induces cell death.
The team treated human rhabdomyosarcoma and human liver cancer cells with celecoxib.
STAT3 has been shown to be elevated in rhabdomyosarcoma and liver cancer cells and plays a crucial role in the growth and survival of these tumors.
They found that celecoxib interrupts STAT3 activation in rhabdomyosarcoma cells leading to inhibition of downstream genes, which ultimately results in cell death. Celecoxib also inhibited formation of clone cell colonies and migration in these cancer cells, properties which could be beneficial in the treatment of malignancies. In addition, using COX-2 negative colon cancer cells, they observed celecoxib can inhibit STAT3 and induce cell death independent of COX-2.
In the liver cancer cell lines, they saw that celecoxib inhibited STAT3 and caused cell death by stopping activation triggered by the pro-inflammatory cytokine, IL-6. IL-6 encourages inflammation and has been implicated as a factor in tumor growth. They also demonstrated that a combination of celecoxib with Sorafenib, the only FDA-approved drug for liver cancer, generated greater anti-liver cancer cell effects than single drug alone. These results suggested the combination of celecoxib and Sorafenib may have a greater anti-liver cancer effect than using Sorafenib alone and may improve the 5-year survival rate of patients with liver cancer.
“It is likely that celecoxib encourages tumor cell death by way of several different pathways in addition to COX-2,” said Jaiyuh Lin, PhD, principal investigator in the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital and Associate Professor at the department of Pediatrics. “Our results indicate that the STAT3 pathway is one of the major COX-2 independent mechanisms.”
Although many STAT3 small molecule inhibitors have been described, very few of them is currently selected for clinical trials for advanced cancer. “These early findings indicate that it may be useful to add the STAT3 pathway to the list of possible treatment targets for rhabdomyosarcoma and liver cancer and as a potential cancer prevention drug for many types of human cancer that have STAT3 activation,” said Dr. Lin. “Also that the combination of celecoxib and Sorafenib may have a greater effect for liver cancer treatment and that celecoxib may be a platform for further development of STAT3 specific small-molecule inhibitors.” Dr. Lin says studies in animal models and humans are needed to test these findings.
Reed S, Li H, Li C, Lin J. Celecoxib inhibits STAT3 phosphorylation and suppresses cell migration and colony forming ability in rhabdomyosarcoma cells. Biochem Biophys Res Commun. 407: 450-455, 2011
Liu Y, Liu A, L, Li H, Li C, Lin J. Celecoxib inhibits constitutive and interleukin 6-induced STAT3 phosphorylation in the human hepatocellular carcinoma cells. Cancer Prevention Research. 2011 Apr 13. [Epub ahead of print]