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Abstract: The hedgehog (Hh) signaling pathways have a crucial role in cell proliferation and survival, and the de-regulation of these pathways can lead to tumorigenesis. Here we investigated the expression and function of these pathways in acute T lymphocytic leukemia cells (T-ALL). Profiling of Hh pathway members revealed common expression of key Hh signaling effectors in all T-ALL cells. We found that T-ALL cells were insensitive to specific Smoothened (SMO) inhibition following the use of low concentrations of the SMO antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT58 reduced expression of the target gene Patched 1 as well as GLI family zinc finger 1 (GLI1) and preferentially decreased the viability of T-ALL cells. We also found perifosine, a novel AKT inhibitor, down-regulated GLI1 protein by dephosphorylation of AKT and GSK3β dose-dependently and that pre-treatment with PD98059, a MEK/ERK pathway inhibitor, enhanced this down-regulation by 20%–30%. Then we questioned whether use of both GANT58 and AKT inhibitor together could confer a synergistic effect to decrease T-ALL cell viability. By applying the Chou–Talalay method, low concentration of GANT58 induced T-ALL cell death in a synergism fashion with perifosine or GSK690693 when used simultaneously. These findings indicate that the combined use of GANT58 and AKT inhibitor could help treat a broad range of malignant tumors in conjunction with existing cancer treatments. [Copyright &y& Elsevier]

Abstract: Oxysterols have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells, while they have little or no effect on senescent cells. The mechanisms by which oxysterols may influence proliferation are manifold: they control the transcription and the turnover of the key enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, by binding to Insig-1, Insig-2 and liver X receptors. Oxysterols are thought to be generated in proportion to the rate of cholesterol synthesis. Although there is no consensus about the mechanism by which these oxysterols are generated in vivo, it clearly has to be ubiquitous. The 25- and the 27-cholesterol hydroxylases, present in almost all tissues, are possible candidates. Cholesterol uptake from lipoproteins, intracellular vesicle transport and lipid transfer are also modified by oxysterols. Oxysterols interfere with ERK, hedgehog and wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, oxysterols invariably both slow down proliferation and provoke cell death. Perhaps is it sufficient to stop proliferation of a cancer to provoke its eradication. Therefore, the two facets of oxysterol action that seem important for cancer treatment, cytostaticity and cytotoxicity, will be discussed. [Copyright &y& Elsevier]

Hedgehog (Hh) is one of the most important signalling pathways. Together with the Wnt, TGF-β/BMP and Notch pathways, it is involved in both embryonic development and adult tissue homeostasis. This is because Hh plays a central role in the proliferative control and differentiation of both embryonic stem cells and adult stem cells. In this way, an alteration in the Hh pathway, either by misexpression of components of that pathway or by changes in the expression of other cellular components that interfere with the Hh signalling system, may trigger the development of several types of cancer. This occurs because normal stem cells or their intermediaries toward differentiated mature cells are not part of the normal proliferative/differentiation balance and begin to expand without control, triggering the generation of the so-called cancer stem cells. In this review, we will focus on the molecular aspects and the role of Hh signalling in normal tissues and in tumour development. [ABSTRACT FROM AUTHOR]