Abstract

Isoliquiritigenin is a chalcone derivative with potential in cancer chemoprevention. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent, some cancer cells are resistant to TRAIL treatment. Current studies have tried to overcome TRAIL-resistant cancer cells. Here, we show for the first time that isoliquiritigenin overcomes TRAIL resistance in colon cancer HT29 cells. HT29 cells were treated with isoliquiritigenin and/or TRAIL, and apoptosis induction was detected by flow cytometry and fluorescence microscopy. Protein expression relating to the TRAIL pathway was analyzed by Western blotting. A single treatment with isoliquiritigenin scarcely induced apoptosis in HT29 cells. Combined treatment with suboptimal concentrations of isoliquiritigenin and TRAIL markedly induced apoptosis, however. The effect was blocked by a pan-caspase inhibitor and a caspase-3, 8, 9, or 10 inhibitor, suggesting that the combination facilitates caspase-dependent apoptosis. Furthermore, the apoptosis induced by isoliquiritigenin and TRAIL was blocked by a dominant negative form of the TRAIL receptor. This result indicates that the combined effect is caused by specific interaction between TRAIL and its receptors. Isoliquiritigenin increased the amount of DR5 protein among TRAIL receptors. Isoliquiritigenin did not significantly increase levels of the Bcl-2 family proteins Bcl-2, Bcl-xL, and BAX. Our results suggest that isoliquiritigenin has the potential to overcome resistance to TRAIL in cancer cells and its chemopreventive effects may depend on TRAIL function.

Highlights

  • The risk of human death is highest from malignant tumors

  • Our results suggest that isoliquiritigenin has the potential to overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells and its chemopreventive effects may depend on TRAIL function

  • In this study we show that isoliquiritigenin increases production of DR5 protein and overcomes resistance to TRAIL in colon cancer HT29 cells

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Summary

Introduction

The risk of human death is highest from malignant tumors. Prevention of malignant tumors is the most important issue in the field of preventive medicine. Many epidemiological studies have attempted to reveal a relationship between foods and carcinogenesis. Foods have been considered to be related to the prevention of carcinogenesis. There is much evidence that dietary components are able to prevent carcinogenesis in animal models [1,2,3]. Isoliquiritigenin is a chalcone derivative contained in edible plants and used as a Chinese herbal medicine. Isoliquiritigenin inhibits aberrant crypt foci from developing [4, 5], skin tumors [6], and pulmonary metastasis of renal cell carcinoma [7] in mice

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