Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling

Abstract

The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.

Statins in Cancer Prevention and Therapy

“…While knockdown or deletion of RhoB slows DNA repair and induces genomic instability [127], increased expression and accumulation of unprenylated RhoB upon statin treatment may or may not have a similar impact. The synergy of fluvastatin with temozolomide in glioblastoma is ascribed to reduced prenylation limiting Ras activation [128,129]. Regarding small cell lung cancer (SCLC), several human chemoresistant xenograft models exposed to long-term intermittent chemotherapy displayed improved outcomes upon statin treatment.…”

The effects of statin therapy on brain tumors, particularly glioma: a review

“…The underlying mechanism of fluvastatin-induced cytotoxicity is not entirely understood. However, molecular experiments revealed a crucial role of fluvastatin in inducing JNK1/2 phosphorylation while inhibiting ERK1/2 phosphorylation [81,[84][85][86]. This modulatory effect of fluvastatin on ERK and JNK activation results in disruptive MAPK pathways in C6 cells [81], leading to apoptosis.…”

“…Even at high doses, fluvastatin exhibited a neurotrophic effect on normal neuron cells, consistent with a reported increase in neurite length and branching of rat hippocampal neurons after treatment with pravastatin [ 82 , 83 ]. Fluvastatin-induced apoptosis in glioma cells is based on the morphological changes such as the presence of rounded and shrunken cells with irregular and pycnotic nuclei and reduced length of cytoplasmic protrusions [ 81 – 84 ]. The underlying mechanism of fluvastatin-induced cytotoxicity is not entirely understood.…”