The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism

Background Hesperidin, a flavanone present in citrus fruits, has been identified as a potent anticancer agent because of its proapoptotic and antiproliferative characteristics in some tumor cells. However, the precise mechanisms of action are not entirely understood. Aim The main purpose of this study is to investigate the involvement of peroxisome proliferator-activated receptor-gamma (PPAR gamma) in hesperidin's anticancer actions in human pre-B NALM-6 cells, which expresses wild-type p53. Methods The effects of hesperidin on cell-cycle distribution, proliferation, and caspase-mediated apoptosis were examined in NALM-6 cells in the presence or absence of GW9662. The expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma), p53, phospho-I kappa B, Bcl-2, Bax, and XIAP proteins were focused on using the immunoblotting assay. The transcriptional activities of PPAR gamma and nuclear factor-kappaB (NF-kappa B) were analyzed by the transcription factor assay kits. The expression of PPAR gamma and p53 was analyzed using the RT-PCR method. Results Hesperidin induced the expression and transcriptional activity of PPAR gamma and promoted p53 accumulation and downregulated constitutive NF-kappa B activity in a PPAR gamma-dependent and PPAR gamma-independent manner. The growth-inhibitory effect of hesperidin was partially reduced when the cells preincubated with PPAR gamma antagonist prior to the exposure to hesperidin. Conclusions The findings of this study clearly demonstrate that hesperidin-mediated proapoptotic and antiproliferative actions are regulated via both PPAR gamma-dependent and PPAR gamma-independent pathways in NALM-6 cells. These data provide the first evidence that hesperidin could be developed as an agent against hematopoietic malignancies.