Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and ß1-triggered motility, migration and invasion of prostate cancer cells.

BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) might become a novel tool to treat advanced prostate cancer. However, chronic drug exposure may trigger resistance, limiting the utility of mTOR inhibitors. METHODS: Metastatic potential of PC3 prostate cancer cells, susceptible (PC3(par)) or resistant (PC3(res)) to the mTOR-inhibitor RAD001 was investigated. Adhesion to vascular endothelium or immobilised collagen, fibronectin and laminin was quantified. Motility, migration and invasion were explored by modified Boyden chamber assay. Integrin α and ß subtypes were analysed by flow cytometry, western blotting and real-time PCR. Integrin-related signalling, EGFr, Akt, p70S6kinase and ERK1/2 activation were determined. RESULTS: Adhesion was reduced, whereas motility, migration and invasion were enhanced in PC3(res). The α2 and ß1 integrin subtypes were dramatically elevated, integrins α1 and α6 were lowered, whereas α5 was nearly lost in PC3(res). Activation of the Akt signalling pathway was strongly upregulated in these cells. Treating PC3(par) cells with RAD001 reduced motility, migration and invasion and deactivated Akt signalling. Blocking studies revealed that α2 and ß1 integrins significantly trigger the motile behaviour of the tumour cells. CONCLUSION: Chronic RAD001 treatment caused resistance development characterised by distinct modification of the integrin-expression profile, driving prostate cancer cells towards high motility.

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro.

BACKGROUND: The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin ß subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose-dependently reduced tumor-cell growth but did not impair tumor-endothelium and tumor-matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated ß1-integrin in PC-3 and diminished ß4-integrin in PC-3 and DU-145 cells. CONCLUSIONS: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

meso-N,N'-oxalyldivaline.

The title compound, 2,2'-(oxalyldiimino)bis(3-methylbutanoic acid), C12H20N2O6, possesses a centre of symmetry. In the crystal, molecules are connected by hydrogen bonds between oxamide and carboxyl groups, similar to the pattern of the monoclinic forms of HO-Gly-CO-CO-Gly-OH and HO-Aib-CO-CO-Aib-OH (Gly is glycine and Aib is 2-aminoisobutyric acid). The characteristic torsion angles in the title compound are close to those in peptide alpha-helices.

Intermolecular contacts in the crystal packing of 2,2'-(N,N'-oxalyldiimino)bis(3-phenylpropanamide) dimethyl sulfoxide solvate.

In the title compound, C20H22N4O4*C2H6OS, two distinct hydrogen-bond systems connect oxalamide groups in one pattern and primary amide groups in the other to form a two-dimensional network perpendicular to the c axis. These hydrophilic layers are joined to the three-dimensional structure through C--H...pi interactions. The hydrogen-bonded waved layers shape holes which are occupied by disordered dimethyl sulfoxide solvent molecules.

Bis(amino acid) oxalyl amides as ambidextrous gelators of water and organic solvents: supramolecular gels with temperature dependent assembly/dissolution equilibrium.

Bis(LeuOH) (1a), bis-(ValOH) (2a) and bis(PhgOH) (5a) (Phg denotes (R)-phenylglycine) oxalyl amides are efficient low molecular weight organic gelators of various organic solvents and their mixtures as well as water, water/DMSO, and water/DMF mixtures. The organisational motifs in aqueous gels are dominated primarily by lipophilic interactions while those in organic solvents are formed by intermolecular hydrogen bonding. Most of the gels are thermoreversible and stable for many months. However, 2a forms unstable gels with organic solvents which upon ageing transform into variety of crystalline shapes. For some 1a/alcohol gels, a linear correlation between alcohol dielectric constants (epsilon) and gel melting temperatures (Tg) was found. The 1H NMR and FTIR spectroscopic investigations of selected gels reveal the existence of temperature dependent network assembly/dissolution equilibrium. In the 1H NMR spectra of gels only the molecules dissolved in entrapped solvent could be observed. By using an internal standard, the concentration of dissolved gelator molecules could be determined. In FTIR spectra, the bands corresponding to network assembled and dissolved gelator molecules are simultaneously present. This enabled determination of the Kgel values by using both methods. From the plots of InKgel versus 1/T, the deltaHgel values of selected gels have been determined (-deltaHgel in 10-36 kJ mol(-1) range) and found to be strongly solvent dependent. The deltaHgel values determined by 1H NMR and FTIR spectroscopy are in excellent agreement. Crystal structures of 2a and rac-5a show the presence of organisational motifs and intermolecular interactions in agreement with those in gel fibres elucidated by spectroscopic methods.