The Evolution of S100B Inhibitors for the Treatment of Malignant Melanoma

Abstract

Malignant melanoma continues to be an extremely fatal cancer due to a lack of viable treatment options for patients. The calcium-binding protein S100B has long been used as a clinical biomarker, aiding in malignant melanoma staging and patient prognosis. However, the discovery of p53 as a S100B target and the consequent impact on cell apoptosis redirected research efforts towards the development of inhibitors of this S100B–p53 interaction. Several approaches, including computer-aided drug design, fluorescence polarization competition assays, NMR, x-ray crystallography and cell-based screens have been performed to identify compounds that block the S100B–p53 association, reactivate p53 transcriptional activities and induce cancer cell death. Eight promising compounds, including pentamidine, are presented in this review and the potential for future modifications is discussed. Synthesis of compound derivatives will likely exhibit increased S100B affinity and mimic important S100B–target dynamic properties that will result in high specificity.

S100B-p53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporin-4 and metalloproteinase-2 inhibition in C6 glioma cells

“…By contrast, BAX protein is known to induce apoptosis in various cell lines (29). In concurrence with the antiproliferative activity of pentamidine described in a number of other cell types, including cultured human melanoma cells (16,17,30,31), the results of the present study indicate that pentamidine treatment dose-dependently increases the BAX/Bcl-2 ratio, demonstrating the pro-apoptotic role of this antiprotozoal agent in cultured glioma cells. The pro-apoptotic effect displayed by pentamidine appears to be directly associated with the inhibition of the S100B-p53 protein-protein interaction, resulting in a marked restoration of wild-type p53 protein function.…”

“…Evidence of S100B/p53 crosstalk, and its impact on cell proliferation and survival, has been the focus of research efforts regarding the development of inhibitors of the S100B-p53 protein-protein interaction. This molecular paradigm represents a novel target for the treatment of the majority of aggressive types of cancer in which S100B protein is highly expressed, such as melanoma (16). For analogous reasons, direct molecular targeting of the S100B protein in glioma appears to be an innovative approach for the development of novel therapeutic interventions against this form of cancer.…”

The S100B story: from biomarker to active factor in neural injury

“…Coherently, the administration of pentamidine, an antiprotozoal drug that also exhibits the intriguing feature of blocking the interaction between S100B and the transcription factor p53 (Hartman et al . ), resulted in attenuation of reactive gliosis and neuronal loss in a mouse model of AD induced by Abeta (1‐42) peptide (Cirillo et al . ).…”

Circulating Biomarkers in Malignant Melanoma

“…S100B inhibits tumor suppressor p53 polymerization and phosphorylation thus inhibiting its function [174]. In fact, this interaction has been studied as a possible target of antitumor treatment and several inhibitors have already been identified [175]. S100B is released by cell death and once in circulation it has a short halflife (30 min) [176].…”