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Genistein (GEN) is a molecule of great interest as a potent chemopreventive agent against atherosclerosis and cancer. However, the bioavailability of GEN is very low in vivo. Our previous study showed that a GEN derivative, 7-difluoromethyl-5,4'-dimethoxygenistein (dFMGEN) has a better bioavailability than GEN in vivo. In this study, we further evaluated the efficacy of dFMGEN as a candidate for cancer therapy. We demonstrated that dFMGEN treatment decreased the viability of A549 cells in a concentration- and time-dependent manner and induced cell-cycle arrest at the G(1) phase. G(1) phase arrest was correlated with a significant reduction of Cdk4 and cyclin D1 protein level. Further studies showed that cyclin-dependent kinase (Cdk)4 and cyclin D1 protein-level decrease was caused by Cdk inhibitors p15, p21, and p27 level increase, and decreased protein level directly suppressed Rb protein phosphorylation and E2F-1 expression, then cell-cycle progression was arrested. Finally, we also found that dFMGEN has a dosage effect in suppressing tumor growth in vivo, and that dFMGEN was well tolerated by animals. In summary, our results suggest that dFMGEN has therapeutic potential for the treatment of human lung cancer.

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a b s t r a c tWe previously demonstrated that 14-3-3r was downregulated in 5-fluorouracil (5-Fu)-resistant MCF-7 breast cancer cells (MCF-7/5-Fu). Here, we found that stably enhanced 14-3-3r expression strengthened the effects of 5-Fu, Mitoxantrone and cDDP. 14-3-3r stabilised the p53 protein and bound Akt to inhibit its activity and its downstream targets: survivin, Bcl-2 and NF-jB-p50. In addition, decreased p53 expression, but not promoter hypermethylation, was responsible for the downregulation of 14-3-3r in MCF-7/5-Fu cells. Meanwhile, initial treatments with high concentrations of 5-Fu clearly induced 14-3-3r and p53 expression in a time-dependent manner. 14-3-3r-mediated molecular events that synergise with p53 may play important roles in the chemotherapy of breast cancer.

Retinoblastoma (RB) is an intraocular malignancy that mainly affects young children. Previous reports have demonstrated that mutations or the inactivation of the RB1 gene were the main cause of RB; however, disruption of the intracellular signaling pathways following deficiency of RB1 requires further investigation. Based on the Gene Expression Omnibus data and bioinformatics prediction, the present study aimed to investigate the microRNA (miR)-338-3p/neuro-oncological ventral antigen 1 (NOVA1) axis in RB. Subsequently, overexpression and knockdown of miR-338-3p and NOVA1, respectively, were performed to study the role of miR-338-3p/NOVA1 in the progression of the RB cells. The results demonstrated that overexpression of miR-338-3p significantly inhibited cell proliferation, migration and invasion, and promoted apoptosis of the RB cells. Moreover, knockdown of NOVA1 showed similar results. A dual-luciferase reporter assay and rescue experiments further confirmed the direct binding between miR-338-3p and NOVA1. Taken together, the results indicated that miR-338-3p acted as tumor suppressor by targeting the oncogene of NOVA1 in RB, which may serve as potential therapeutic targets in RB.