Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Targeting PVR (CD155) and its receptors in anti-tumor therapy

Poliovirus receptor (PVR, CD155) has recently been gaining scientific interest as a therapeutic target in the field of tumor immunology due to its prominent endogenous and immune functions. In contrast to healthy tissues, PVR is expressed at high levels in several human malignancies and seems to have protumorigenic and therapeutically attractive properties that are currently being investigated in the field of recombinant oncolytic virotherapy. More intriguingly, PVR participates in a considerable number of immunoregulatory functions through its interactions with activating and inhibitory immune cell receptors. These functions are often modified in the tumor microenvironment, contributing to tumor immunosuppression. Indeed, increasing evidence supports the rationale for developing strategies targeting these interactions, either in terms of checkpoint therapy (i.e., targeting inhibitory receptors) or in adoptive cell therapy, which targets PVR as a tumor marker

The Glial Differentiation Factor Nuclear Factor One B (Nfib) Induces Differentiation and Inhibits Growth of Glioblastoma.

International audienceThe molecule CD90 is a N-glycosylated, glycophosphatidylinositol anchored cell surface protein, originally described on thymocytes. CD90 has been considered as a surrogate marker for a variety of stem cells and has recently been reported on glioblastoma stem cells. CD90 is also expressed on T lymphocytes, endothelial cells, fibroblasts and neurons. The function of CD90 is not fully elucidated. CD90 has been involved in cell-cell and cell-matrix interactions, in neurite outgrowth, T cell activation and apoptosis. In this study, we confirmed the expression of CD90 on human glioblastoma stem-like cells from serum-free neurosphere cultures. We also observed RNA and protein CD90 expression on primary cell lines from FSC-containing culture (adherent cell lines) and on freshly prepared glioblastoma specimen. In order to study the function of CD90 on glioblastoma cells, we used a silencing strategy to decrease the expression of CD90 on the immortalized U251 cell line. We then compared the viability, the tumor growth and the migration property of the wild-type CD90+ U251 cells and CD90 down-regulated U251 clones. The decrease of CD90 expression did not affect the viability and the tumor growth of U251 cells. In contrast, down-regulation of CD90 mediated the decreased ability of tumor cell migration using both scratch wound healing and boyden chamber migration assays. Experiments are currently on going to test the effect of CD90 expression on tumorigenicity in mice models. In total, this study might lead to better understand the role of CD90 on the pathology in particular in term of tumor migration/invasion of human glioblastoma