Combination Effect of Equol and TRAIL against Human Cervical Cancer Cells

Background/Aim: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy due to its selective ability to induce apoptosis of cancer cells. However, some cancer cells are resistant to TRAIL. Here, we demonstrated that treatment with TRAIL, in combination with equol, sensitizes TRAIL- mediated apoptosis of HeLa cells. Materials and Methods: Cell viability was evaluated by the colorimetric cell viability assay (MTT). Apoptotic cell death was analyzed by flow cytometry and microscopy. Western blotting was performed to examine protein expression and cell surface expression was evaluated by flow cytometry. Enzymatic activity of caspases was measured by the colorimetric assay. Results: Equol enhanced TRAIL-induced apoptosis through activation of caspase-3, -8, -9, and cleavage of BID. Furthermore, DR4/Fc chimera protein and DR5/Fc chimera protein efficiently reduced the activation of caspases and BID cleavage, as well as apoptotic cell death induced by co- treatment with equol and TRAIL. Conclusion: Equol enhances TRAIL-induced apoptosis of HeLa cells through a death receptor-mediated caspase pathway. Cervical cancer is the second most common type of cancer in women, and is the most frequent female malignancy in developing countries (1). Although the worldwide death rates from cervical cancer have decreased, it remains the leading cause of mortality for women in developing countries (2). Although conventional treatments, such as surgery, radiation, and chemotherapy are used effectively, the survival benefit is limited, and relapse can occur after treatment (3). Therefore, new therapeutic options are needed in order to improve the treatment of cervical cancer. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, has been considered as an attractive anticancer agent, as it preferentially induces apoptosis of malignant or transformed