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Time-dependent simvastatin administration enhances doxorubicin toxicity in neuroblastoma.

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, 10?M was chosen as the intervention concentration. We found that significant cell death resulted from 1.0?M 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.

SUBMITTER: Anderson CC

PROVIDER: S-EPMC7184108 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Time-dependent simvastatin administration enhances doxorubicin toxicity in neuroblastoma.

Anderson Colin C CC Khatri Meera M Roede James R JR

Toxicology reports 20200422

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 stat ...[more]

PMID: 32368502

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Project description:High-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate of less than 40%. Therefore, new agents are urgently needed to overcome chemotherapy resistance so as to improve the treatment outcome of this deadly disease. Histone deacetylase (HDAC) inhibitors (HDACIs) represent a novel class of anticancer drugs. Recent studies demonstrated that HDACIs can down-regulate the CHK1 pathway by which cancer cells can develop resistance to conventional chemotherapy drugs. This prompted our hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs for treating neuroblastoma would result in enhanced anti-tumor activities of these drugs. Treatment of high-risk neuroblastoma cell lines with a novel pan-HDACI, panobinostat (LBH589), resulted in dose-dependent growth arrest and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the combination of panobinostat with cisplatin, doxorubicin, or etoposide resulted in highly synergistic antitumor interactions in the high-risk neuroblastoma cell lines, independent of the sequence of drug administration. This was accompanied by cooperative induction of apoptosis. Furthermore, panobinostat treatment resulted in substantial down-regulation of CHK1 and its downstream pathway and abrogation of the G2 cell cycle checkpoint. Synergistic antitumor interactions were also observed when the DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. Contrary to panobinostat treatment, LY2603618 treatments neither resulted in abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma cells. Surprisingly, LY2603618 treatments caused substantial down-regulation of total CDK1. Despite this discrepancy between panobinostat and LY2603618, our results indicate that suppression of the CHK1 pathway by panobinostat is at least partially responsible for the synergistic antitumor interactions between panobinostat and the DNA damaging agents in high-risk neuroblastoma cells. The results of this study provide a rationale for clinical evaluation of the combination of panobinostat and cisplatin, doxorubicin, or etoposide for treating children with high-risk neuroblastoma.

Project description:Tuberculosis remains a serious threat worldwide. For this reason, it is necessary to identify agents that shorten the duration of treatment, strengthen the host immune system, and/or decrease the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and have immunomodulatory, anti-inflammatory and antimicrobial effects. Although there is evidence that statins may contribute to the containment of Mycobacterium tuberculosis infection, their effects on peripheral blood mononuclear cells (PBMCs) involved in the immune response have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via flow cytometry and confocal microscopy. Simvastatin decreased the growth of M. tuberculosis in PBMCs, increased the proportion of NKT cells in culture, increased the expression of co-stimulatory molecules in monocytes, promoted the secretion of the cytokines IL-1β and IL-12p70, and activated apoptosis and autophagy in monocytes, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.

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Dataset Information

Time-dependent simvastatin administration enhances doxorubicin toxicity in neuroblastoma.

Publications

Time-dependent simvastatin administration enhances doxorubicin toxicity in neuroblastoma.

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