(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Brain-Neoplasms

Fluvastatin is a member of the family of HMG-CoA reductase inhibitors (statins) extensively used in medical practice. Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development. The aim of the present study was to investigate the anti-cancer potential of fluvastatin in C6 rat malignant glioma cells.. First, the effects of fluvastatin on cell viability (MTT assay), proliferation (BrdU assay), cell morphology, and cytoskeleton were examined. Subsequently, its effect on extracellular signal regulated kinase 1 and 2 (ERK1/2) and c-Jun N-terminal kinase 1 and 2 (JNK 1/2) expression was estimated by Western blot. Finally, the influence of fluvastatin on cell migration and production of MMP-9 and VEGF was determined using a wound-healing assay and ELISA test, respectively.. The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor C6 cells (IC(50) = 8.6 μM, 48 h), but did not inhibit the growth of normal neuronal cells. The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm, chromatin condensation, and nucleus breakdown.. The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p-ERK1/2 expression, upregulation of p-JNK1/2, and reduction in the MMP-9 and VEGF concentrations in culture media. The high anticancer (antiproliferative, proapoptotic, antiinvasive) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cytoskeleton; Extracellular Signal-Regulated MAP Kinases; Fatty Acids, Monounsaturated; Fluvastatin; Glioma; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; Rats; Vascular Endothelial Growth Factor A

Pilocytic astrocytomas occur predominantly in childhood. In contrast to the posterior fossa location, hypothalamo-chiasmatic pilocytic astrocytomas display a worse prognosis often leading to multiple surgical procedures and/or several lines of chemotherapy and radiotherapy to achieve long-term control. Hypothalamo-chiasmatic pilocytic astrocytomas and cerebellar pilocytic astrocytomas have a distinctive gene signature and several differential expressed genes (ICAM1, CRK, CD36, and IQGAP1) are targets for available drugs: fluvastatin and/or celecoxib.. Quantification by RT-Q-PCR of the expression of these genes was performed in a series of 51 pilocytic astrocytomas and 10 glioblastomas: they were all significantly overexpressed in hypothalamo-chiasmatic pilocytic astrocytomas relative to cerebellar pilocytic astrocytomas, and CRK and ICAM1 were significantly overexpressed in pilocytic astrocytomas versus glioblastomas.We used two commercially available glioblastoma cell lines and three pilocytic astrocytoma explant cultures to investigate the effect of celecoxib/fluvastatin alone or in combination. Glioblastoma cell lines were sensitive to both drugs and a combination of 100 μM celecoxib and 240 μM fluvastatin was the most synergistic. This synergistic combination was used on the explant cultures and led to massive cell death of pilocytic astrocytoma cells.As a proof of concept, a patient with a refractory multifocal pilocytic astrocytoma was successfully treated with the fluvastatin/celecoxib combination used for 18 months. It was well tolerated and led to a partial tumor response.. This study reports evidence for new targets and synergistic effect of celecoxib/fluvastatin combination in pilocytic astrocytoma. Because it is non-toxic, this new strategy offers hope for the treatment of patients with refractory pilocytic astrocytoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; CD36 Antigens; Celecoxib; Cell Line, Tumor; Child, Preschool; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Synergism; Fatty Acids, Monounsaturated; Female; Fluvastatin; Gene Expression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Intercellular Adhesion Molecule-1; Proto-Oncogene Proteins c-crk; Pyrazoles; ras GTPase-Activating Proteins; Sulfonamides; Tissue Culture Techniques