Abstract
Medulloblastoma is a common pediatric brain tumor and one of the main types of solid cancers in children below the age of 10. Recently, cholesterol-lowering “statin” drugs have been highlighted for their possible anti-cancer effects. Clinically, statins are reported to have promising potential for consideration as an adjuvant therapy in different types of cancers. However, the anti-cancer effects of statins in medulloblastoma brain tumor cells are not currently well-defined. Here, we investigated the cell death mechanisms by which simvastatin mediates its effects on different human medulloblastoma cell lines. Simvastatin is a lipophilic drug that inhibits HMG-CoA reductase and has pleotropic effects. Inhibition of HMG-CoA reductase prevents the formation of essential downstream intermediates in the mevalonate cascade, such as farnesyl pyrophosphate (FPP) and gernaylgerany parophosphate (GGPP). These intermediates are involved in the activation pathway of small Rho GTPase proteins in different cell types. We observed that simvastatin significantly induces dose-dependent apoptosis in three different medulloblastoma brain tumor cell lines (Daoy, D283, and D341 cells). Our investigation shows that simvastatin-induced cell death is regulated via prenylation intermediates of the cholesterol metabolism pathway. Our results indicate that the induction of different caspases (caspase 3, 7, 8, and 9) depends on the nature of the medulloblastoma cell line. Western blot analysis shows that simvastatin leads to changes in the expression of regulator proteins involved in apoptosis, such as Bax, Bcl-2, and Bcl-xl. Taken together, our data suggests the potential application of a novel non-classical adjuvant therapy for medulloblastoma, through the regulation of protein prenylation intermediates that occurs via inhibition of the mevalonate pathway.
Highlights
Medulloblastoma is a common primary pediatric brain tumor that comprises about 15–20% of pediatric brain tumors
To examine the possible cell death effects of simvastatin in medulloblastoma cells, Daoy, D283, and D341 cell lines were treated with 0.5–20 μM simvastatin at different time points [0–96 h (24 h, 48 h, 72 h, and 96 h)] (Figure 1A–C)
Sub-G1 population analysis of the results indicated a significant increase in the percentage of apoptotic cells in Daoy (p < 0.0001) (Figure 2E), D283 (p < 0.01) (Figure 2F), and D341 (p < 0.001)
Summary
Medulloblastoma is a common primary pediatric brain tumor that comprises about 15–20% of pediatric brain tumors. Medulloblastoma originates from the posterior part of the brain and cerebellum, which is an important brain structure with specific mature and immature cell types that are controlled at several levels [1,2,3,4]. 3–9 years of age in children, with 10% of cases in young infants. There are four medulloblastoma subgroups, which have distinguishing features, and include: Wingless-INT (WNT), Sonic Hedgehog (SHH), subgroup 3, and subgroup 4 [5]. Current treatments for medulloblastoma include radiation, chemotherapy, and surgery [6,7,8,9]. Radiation therapy has strict limitations, as it is usually contraindicated in young children, due to its adverse effects on brain development at a young age [10]
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