The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.

Ring1 and YY1 binding protein (RYBP) is a member of Polycomb group (PcG) proteins and regulates cell growth through both PcG-dependent and -independent mechanisms. Our initial study indicated that RYBP is down-regulated in human non-small cell lung cancer (NSCLC) tissues. The present study determined the molecular role of RYBP in the development of NSCLC. We systemically investigated the association between the RYBP expression and the survival of patients with NSCLC. We also carried out in vitro and in vivo studies to explore the molecular basis for the tumor suppressing role of RYBP in NSCLC. Our clinical results demonstrated that the RYBP mRNA and protein expressions were significantly down-regulated in NSCLC and significantly linked to the poor prognosis in NSCLC patients. The enforced expression of RYBP inhibited cell survival, induced apoptosis, and increase chemosensitivity in NSCLC cells; knockdown of RYBP showed the opposite effects. Moreover, adenoviral delivery of RYBP sensitized the NSCLC cells to chemotherapy in vivo. In addition, RYBP expression was induced by paclitaxel, the first-line chemotherapeutic agent for NSCLC. Our results reveal that RYBP inhibits the aggressiveness of NSCLC cells and downregulation of RYBP is associated with poor prognosis,, suggesting that RYBP could be developed as a biomarker and a novel target for therapy in patients with lung cancer.

The transcription factor NFAT1 and the oncogene MDM2 have crucial roles in breast cancer development, progression, and metastasis. We have recently discovered that NFAT1 activates MDM2 expression. Here, we identified a small molecule (named Inulanolide A) that dually inhibited both NFAT1 and MDM2 in breast cancer cells in vitro and in vivo. Unlike conventional MDM2 inhibitors, Inulanolide A (InuA) exerted its selective anticancer activity in both p53-dependent and -independent manners. InuA decreased cell proliferation and induced G2/M phase arrest and apoptosis in breast cancer cells; it also led to a decrease in MDM2, NFAT1 and proteins associated with cell proliferation, and an increase in apoptotic signal related proteins. In a mouse orthotopic model, JapA suppressed tumor growth and lung metastasis without host toxicity. Thus, InuA is a novel NFAT1 and MDM2 dual targeting agent and may be a clinical candidate for breast cancer therapy. This study also validates the effectiveness of dually targeting NFAT1 and MDM2 in breast cancer.