Statins: A New Approach to Combat Temozolomide Chemoresistance in Glioblastoma

Shojaei, Shahla; Alizadeh, Javad; Thliveris, James A.; Koleini, Navid; Kardami, Elissavet; Hatch, Grant M.; Xu, Fred Y.; Hombach‐Klonisch, Sabine; Klonisch, Thomas; Ghavami, Saeid

doi:10.1136/jim-2018-000874

Cited by 37 publications

(30 citation statements)

References 85 publications

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“…Epidemiological studies have shown that the long-term consumption of statins reduces mortality rates of different types of cancer, including GBM (it is worth mentioning that in GBM, it reduces the mortality but is not statistically significant) [ 13 , 14 ]. In addition, preclinical studies have confirmed the anticancer, anti-proliferative, and anti-metastatic properties of statins in several cancers such as myeloma, leukemia, glioma, breast, and prostate cancer [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

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Section: Introductionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

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“…Decreased responsiveness of GBM cells to TMZ due to drug‐resistance is a major problem in the management of the GBM resulting in fatal outcome. Long‐term use of statins is associated with an increased survival rate of patients with different types of cancers , including GBM , but the underlying molecular mechanisms are unclear. Current cancer chemotherapeutic approaches have failed to achieve desired clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

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“…Glioblastoma Multiforme (GBM) is among the most aggressive and lethal malignancies in humans [1]; it is a devastating brain disease, which typically results in mortality within 15 months postdiagnosis due to elevated intracranial pressure and interruption of normal functioning of brain tissues [2][3][4]. In addition, GBM grows fast and can spread quickly [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

Sharifzad

Mardpour

et al. 2020

IJMS

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Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein 70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intracranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2-treated NK cells as compared to those subjected to nontreated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2-treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

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Statins: A New Approach to Combat Temozolomide Chemoresistance in Glioblastoma

Cited by 37 publications

References 85 publications

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

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