Hesperidin Induces Apoptosis by Inhibiting Sp1 and Its Regulatory Protein in MSTO-211H Cells

Hesperidin, a flavanone present in citrus fruits, has been studied as potential therapeutic agents that have anti-tumor activity and apoptotic effects in several cancers, but there is no report about the apoptotic effect of hesperidin in human malignant pleural mesothelioma through the specificity protein 1 (Sp1) protein. We investigated whether hesperidin inhibited cell growth and regulated Sp1 target proteins by suppressing the levels of Sp1 protein in MSTO-211H cells. The IC(50) value of hesperidin was determined to be 152.3 μM in MSTO-211H cells for 48 h. Our results suggested that hesperidin (0-160 μM) decreased cell viability, and induced apoptotic cell death. Hesperidin increased Sub-G(1) population in MSTO-211H cells. Hesperidin significantly suppressed mRNA/protein level of Sp1 and modulated the expression level of the Sp1 regulatory protein such as p27, p21, cyclin D1, Mcl-1, and survivin in mesothelioma cells. Also, hesperidin induced apoptotic signaling including: cleavages of Bid, caspase-3, and PARP, upregulation of Bax, and down-regulation of Bcl-(xl) in mesothelioma cells. These results show that hesperidin suppressed mesothelioma cell growth through inhibition of Sp1. In this study, we demonstrated that Sp1 acts as a novel molecular target of hesperidin in human malignant pleural mesothelioma.