Abstract
Statins have a primary indication for the reduction and management of hypercholesterolemia; however, evidence shows that statins have the ability to increase the toxicity of chemotherapeutics within cancer cells by inducing anti-proliferative, anti-metastatic, and anti-angiogenic effects. More recently, lipophilic statins have shown complex interaction with energy metabolism, specifically acute mitochondrial dysfunction and delayed inhibition of glycolysis. With the goal to demonstrate that statin-mediated enhancement of chemotherapeutics is time-dependent, we hypothesized that the lipophilic statin simvastatin, in conjunction with variable co-exposure of doxorubicin or cisplatin, will enhance the toxicity of these drugs in neuroblastoma. Utilizing human SK-N-AS neuroblastoma cells, we assessed cell proliferation, necrosis, caspase activation, and overall apoptosis of these cells. After determining the toxicity of simvastatin at 48 h post-treatment, 10μM was chosen as the intervention concentration. We found that significant cell death resulted from 1.0μM dose of doxorubicin with 24 h pre-treatment of simvastatin. On the other hand, simvastatin enhancement of cisplatin toxicity was only observed in the co-exposure model. As doxorubicin has strict dosage limits due to its primary off-target toxicity in cardiac muscle, we further compared the effects of this drug combination on rat H9C2 cardiomyoblasts. We found that simvastatin did not enhance doxorubicin toxicity in this cell line. We conclude that simvastatin provides time-dependent sensitization of neuroblastoma cells to doxorubicin toxicity, and our results provide strong argument for the consideration of simvastatin as an adjuvant in doxorubicin-based chemotherapy programs.
Highlights
Statins are a highly popular class of 3-hydroxy-3-methylglutarylCoA (HMG-CoA) reductase (HMGCR) inhibitors for the treatment of hypercholesterolemia [1]
DOX induced toxicity in these cells at a much lower concentration compared to simvastatin, with inhibition of proliferation occurring as low as 2.5μM (Fig. 1D)
In a separate report that year, they expanded with co-administration of simvastatin and common chemotherapeutic agents from myeloma in vitro [25]
Summary
Statins are a highly popular class of 3-hydroxy-3-methylglutarylCoA (HMG-CoA) reductase (HMGCR) inhibitors for the treatment of hypercholesterolemia [1]. Published studies show the potential of statins as anti-cancer agents via promotion of anti-proliferative effects in certain cancers [2]. Chan et al report that the primary anti-cancer mechanism involves apoptosis via the depletion of geranylgeranylated proteins as a down-stream effect of mevalonate pathway inhibition. Simvastatin acts within neuroblastoma through several distinct pathways including inhibition of the mevalonate pathway, depletion of the vital mitochondrial electron transport substrate Coenzyme Q10 (CoQ10), as well as inhibiting the glycosylation/prenylation of important membrane proteins (i.e. dolichol, a product of the HMG-CoA reductase pathway) [3,4]. In the most general sense, inhibiting HMGCR depletes cells of de novo cholesterol synthesis that is vital for cancer proliferation
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