NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

INTRODUCTION:Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.METHODS:The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.RESULTS:We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion � hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.CONCLUSION:NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials

Plant community attributes affect dry grassland orchid establishment

Several factors have been taken into account to explain the distribution of orchid species. We explored the extent to which plant community attributes affect the abundance and reproductive fitness of three orchid species (Anacamptis morio, Himantoglossum adriaticum and Ophrys sphegodes), native to dry grasslands. Structural attributes of plant community (e.g. cover and height) were assessed in ninety 4 m(2) plots scattered on three hill massifs of the Veneto Region (NE Italy). For the three target orchid species, the height of the flowering stalk, the relative ramet height and the number of flowers and fruits were recorded in 203 tagged ramets. Generalized Linear Model revealed that plant community attributes such as cover and height of the herb layer exert a negative effect on the abundance of orchid populations. Furthermore, regression models indicated that O. sphegodes and H. adriaticum reproductive fitness, determined as fruit/flower ratio, was positively affected by relative ramet height. Our results revealed that local herbaceous vegetation structure influences the cover and fruit set of target orchid species. However, there can be substantial variation in the response of different species and variation in the structural attributes of surrounding vegetation may be associated with differences in the strength of selection. In order to achieve effective results in orchid species conservation, protocols for the in situ conservation must detail the range of vegetation covers and heights at which orchid species are favoured and can produce the most effective inflorescences