The results showed that in vitro efficacy did not always match in viv

Several drugs and synthetic or natural compounds have been reported to inhibit and modulate catenin signaling, however, their detailed mechanisms are little understood. Imatinib These small molecule inhibitors may act by reducing catenin stability, blocking catenin TCF interaction or catenin CREB binding protein interaction, stabilizing Axin2 level, preventing dishevelled Frizzled interaction, or other indirect inhibition. Here, we found that ovatodiolide reduced phosphorylation of AKT and therefore downregulated the phosphorylation of its downstream molecules GSK3and catenin in RCC cell lines. Reduced phosphorylation of GSK3prolongs GSK3activation and decreases catenin protein stability. Reduced phosphorylation of catenin inhibits catenin activation and nuclear signaling.

We found that ovatodiolide significantly downregulated survivin in RCC cells both in vitro and in vivo. As in Figure S5C, schematic Urogenital pelvic malignancy diagram depicts the mechanism of inactivation of catenin by ovatodiolide in RCC cells. Survivin knockdown has been associated with G2/M arrest, which may explain why catenin signaling inhibitors induced G2/M arrest, although it has also been associated with Axin2 reduction. Combined treatment with ovatodiolide and sorafenib or sunitinib overcame drug resistance in TKI resistant RCC cells. Sorafenib and sunitinib are approved for treatment of advanced RCC by the US Food and Drug Administration. Both have been reported asmultikinase inhibitors of vascular endothelial growth factor receptor, platelet derived growth factor receptor, RAF, and several different tyrosine kinases and therefore are used in treating several cancers.

RCC patients treatedwith these TKIs showprolonged progressionfree survival and/or overall pifithrin-? survival, but resistance to therapy is inevitable. Despite permanent genetic or epigenetic changes in the tumor or selection of drug resistant clones, resistance of these TKIs is attributed to resumption of angiogenesis, or angiogenic escape, according to reversible gene expression in the tumor and/or its microenvironment or accompanied by alternative signaling pathways such as reduction in level of interferon related angiostatic chemokines. Current strategies to maximize the effectiveness of treatment have mostly focused on sequential, combination, adjuvant, or novel targeted therapy.

We also found that RAS RAF MEK1 ERK1 signaling is reversibly expressed in sorafenib or sunitinib resistant 786 O and ACHN cells. In addition, we found reversed phosphorylated STAT3 status, another target of these TKIs in different cancer types. After combined treatment of ovatodiolide with sorafenib or sunitinib, the reversible gene expressionwas abrogated and the cytotoxic responsewas greater than in controls. The catenin signaling dysregulation involved in the drug resistance of RCC cells and the synergistic effects of catenin signaling inhibitors and TKIs may be useful to enhance the treatment response of highly chemorefractory, advanced RCC.