Dr John on the Antitumor Effects of Sulindac in an Obesity-Driven Model of Endometrial Cancer

Catherine John, MD, fellow, gynecologic oncology, Department of Obstetrics and Gynecology, University of North Carolina Chapel Hill School of Medicine, discusses the antitumor effects of sulindac (Clinoril) on the prevention and treatment of obesity-driven models of endometrial cancer.

Obesity is a major risk factor for the development of endometrial cancer due to its induction of a chronic, low-grade inflammatory state which can promote tumor growth. Therefore, the increasing incidence of obesity has been associated with higher mortality rates in endometrial cancer.

The nonsteroidal anti-inflammatory drug (NSAID) sulindac previously demonstrated beneficial antitumor activity in preclinical models of obesity-driven gastrointestinal cancers by downregulating COX-1 and COX-2 expression. A study was conducted to evaluate the agent's effect on tumor pathogenesis and development in obesity-driven endometrial cancer. In the study, investigators utilized both human endometrial cancer cell lines and a transgenic mouse model of endometrioidendometrial cancer.

In the KLE and HEC-1 human cell lines, exposure to sulindac at varying concentrations was found to induce apoptosis through an increase in pro-apoptotic proteins, decreased cell proliferation, and increased cellular stress, John reports. The agent prevented cell invasion with migratory proteins and cell-adhesion proteins, and decreased the expression of cell cycle proteins, she adds.

Sulindac was shown to reduce tumor growth in the Lkb1/flp53fl/fl mouse model, John continues. Notably, tumor weight was highly decreased in mice that were administered a high-fat diet, signifying that these anti-tumorigenic and anti-proliferative effects are most pronounced in the obesity setting. The agent’s ability to downregulate both Ki-67 and COX-2 expression in vivo was also confirmed, John concludes. Next steps for this research should aim to assess the viability of sulindac in the treatment of patients with endometrial cancer.