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Object: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a ‘double haemorrhage’ rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. Methods and Results: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-α and PKC-β and calcium-independent PKC-η and PKC-ζ in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-η, and those of S100A1 with PKC-β. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-η, and those of S100B with PKC-ζ. Conclusion: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm. [ABSTRACT FROM AUTHOR]

Lubansu A, Ruchoux M-M, Brotchi J, Salmon I, Kiss R & Lefranc F (2003) Histopathology 43, 563–572 Cathepsin B, D and K expression in adamantinomatous craniopharyngiomas relates to their levels of differentiation as determined by the patterns of retinoic acid receptor expression To investigate the potential predictive value of cathepsins B, D and K in a series of 51 adamantinomatous craniopharyngiomas. While almost always benign, craniopharyngiomas exhibit a high propensity to recur postsurgically and biological markers are therefore needed to predict their recurrence. We have previously demonstrated the potential predictive value of retinoic acid receptors (RARs) (Lefranc et al., J. Neurosurg. 2003; 98; 145–153). Computer-assisted microscopy was used to determine quantitatively the immunohistochemical levels of expression of the α, β and γ RAR subtypes and cathepsins B, D and K. The levels of expression of cathepsin D and of cathepsin B correlated significantly with the levels of expression of RARβ. The levels of expression of cathepsin K correlated significantly with the levels of expression of RARγ. Recurrent adamantinomatous craniopharyngiomas are characterized by low levels of RARβ and high levels of RARγ. The tendency to recurrence seems, at least partly, to relate to the fact that (i) craniopharyngiomas with low levels of RARβ express low levels of cathepsin D, and (ii) craniopharyngiomas with high levels of RARγ express high levels of cathepsin K. [ABSTRACT FROM AUTHOR]

Aims: To investigate whether epidermoid cysts, branchial cysts, craniopharyngiomas and cholesteatomas express S100 proteins differentially by immunohistochemical assaying the presence of S100A1, S100A2, S100A3, S100A4, S100A5, S100A6 and S100B. Methods and results: Immunopositivity/negativity was recorded for each S100 protein in a series of 52 cases consisting of 12 epidermoid cysts, 12 branchial cysts, 15 adamantinomatous craniopharyngiomas and 13 acquired cholesteatomas. Except in the case of the craniopharyngiomas, immunoreactivity was assessed independently in the basal membrane and the basal, the internal and the keratin layers. Our data show that in contrast to S100B, which was rarely expressed, S100A1, S100A2, S100A4 and S100A5 were often present in these four types of epithelial lesions. S100A3 and S100A6 and, to a lesser extent, S100A5 were the most differentially expressed proteins across the different histopathological groups analysed. These three proteins are expressed more often in craniopharyngiomas and cholesteatomas, the two more aggressive types of lesions. Conclusions: This is the first study to report data on the expression of seven S100 proteins in different histopathological groups of epithelial head and neck lesions, whose precise embryological origins are still a matter of debate. S100 proteins could possibly be used as markers to target this embryonic origin, since our results show that S100A3 and S100A6 (and, to a lesser extent, S100A5) are expressed differentially across these different groups of epithelial lesions. [ABSTRACT FROM AUTHOR]

The computer‐assisted microscopic analysis of Feulgen‐stained nuclei enabled us to identify two subgroups of astrocytomas (WHO grade II) and two subgroups of anaplastic astrocytomas (WHO grade III) with significantly distinct clinical outcomes (Decaestecker et’al. Brain Pathol 1998; 8: 29–38). The astrocytomas labelled in the present study as typical (TYP‐ASTs) behaved clinically like real astrocytomas while atypical astrocytomas (ATYP‐ASTs) behaved similarly to anaplastic astrocytomas. The anaplastic astrocytomas that we labelled as typical (TYP‐ANAs) behaved clinically like anaplastic astrocytomas while atypical ones (ATYP‐ANAs) behaved like glioblastomas. In the present study, we investigate whether some biological characteristics could be evidenced across these four groups of TYP‐ and ATYP‐ASTs and TYP‐ and ATYP‐ANAs. The data show that the levels of expression (immunohistochemically assayed and quantitatively determined by means of computer‐assisted microscopy) of vimentin, the glial fibrillary acidic protein and the platelet‐derived growth factor‐α did not differ significantly across these four groups of astrocytic tumours. The level of cell proliferation (determined by means of both the anti‐proliferating cell nuclear antigen and the anti‐MIB‐1 antibodies; P < 0.001 to P < 0.0001) differed very significantly between the astrocytomas and anaplastic astrocytomas, but not between the typical and atypical variants identified in each group. In sharp contrast, the levels of expression of the S100A3 and S100A5 proteins differed markedly in the solid tumour tissue in relation to the astrocytic tumour types and grades. In addition, while the levels of expression of S100A6 did not change in the astrocytic tumour tissue in relation to histopathological grade, the levels of expression of this S100 protein (but not those of S100A3 and S100A5) differed markedly in the blood vessel walls according to whether these vessels originated from low‐ or high‐grade astrocytic tumours. [ABSTRACT FROM AUTHOR]

Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Melanomas remain associated with dismal prognosis because they are naturally resistant to apoptosis and they markedly metastasize. Up-regulated expression of sodium pump alpha sub-units has previously been demonstrated when comparing metastatic to non-metastatic melanomas. Our previous data revealed that impairing sodium pump alpha1 activity by means of selective ligands, that are cardiotonic steroids, markedly impairs cell migration and kills apoptosis-resistant cancer cells. The objective of this study was to determine the expression levels of sodium pump alpha sub-units in melanoma clinical samples and cell lines and also to characterize the role of alpha1 sub-units in melanoma cell biology. Quantitative RT-PCR, Western blotting and immunohistochemistry were used to determine the expression levels of sodium pump alpha sub-units. In vitro cytotoxicity of various cardenolides and of an anti-alpha1 siRNA was evaluated by means of MTT assay, quantitative videomicroscopy and through apoptosis assays. The in vivo activity of a novel cardenolide UNBS1450 was evaluated in a melanoma brain metastasis model. Our data show that all investigated human melanoma cell lines expressed high levels of the alpha1 sub-unit, and 33% of human melanomas displayed significant alpha1 sub-unit expression in correlation with the Breslow index. Furthermore, cardenolides (notably UNBS1450; currently in Phase I clinical trials) displayed marked anti-tumour effects against melanomas in vitro. This activity was closely paralleled by decreases in cMyc expression and by increases in apoptotic features. UNBS1450 also displayed marked anti-tumour activity in the aggressive human metastatic brain melanoma model in vivo. The alpha1 sodium pump sub-unit could represent a potential novel target for combating melanoma.