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

doi:10.1111/febs.15069

. 2020 Mar;287(5):1005-1034.

doi: 10.1111/febs.15069. Epub 2019 Oct 14.

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

Shahla Shojaei^{1

2

3

4}, Navid Koleini^{5

6}, Ehsan Samiei^{2

3

4}, Mahmoud Aghaei^{1

7}, Laura K Cole⁸, Javad Alizadeh¹, Md Imamul Islam⁹, Amir-Reza Vosoughi¹, Mohammed Albokashy¹, Yaron Butterfield^{10

11}, Hassan Marzban¹, Fred Xu⁸, James Thliveris¹, Elissavet Kardami^{1

5}, Grant M Hatch⁸, Eftekhar Eftekharpour⁹, Mohsen Akbari^{2

3

4}, Sabine Hombach-Klonisch¹, Thomas Klonisch^{1

12}, Saeid Ghavami^{1

12

13

14}

Affiliations

¹ Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
² Laboratory for Innovation in Microengineering (LiME), Department of Mechanical Engineering, University of Victoria, Canada.
³ Center for Biomedical Research, University of Victoria, Canada.
⁴ Center for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Canada.
⁵ Institute of Cardiovascular Sciences, St-Boniface Hospital Albrechtsen Research Centre Winnipeg, Canada.
⁶ Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
⁷ Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
⁸ Department of Pharmacology & Therapeutics, Center for Research and Treatment of Atherosclerosis, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
⁹ Regenerative Medicine Program, Spinal Cord Research Centre, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada.
¹⁰ Genome Sciences Centre, BC Cancer, Vancouver, Canada.
¹¹ Patient Advocate and Research Committee, Brain Tumour Foundation of Canada, Ottawa, Canada.
¹² Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
¹³ Biology of Breathing, Children Hospital Research Institute of Manitoba, Max Rady College of Medicine, Rady Faculty of Health Sciences, Winnipeg, Canada.
¹⁴ Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Iran.

PMID: 31545550
DOI: 10.1111/febs.15069

Free article

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

Shahla Shojaei et al. FEBS J. 2020 Mar.

Free article

. 2020 Mar;287(5):1005-1034.

doi: 10.1111/febs.15069. Epub 2019 Oct 14.

Authors

Affiliations

¹ Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
² Laboratory for Innovation in Microengineering (LiME), Department of Mechanical Engineering, University of Victoria, Canada.
³ Center for Biomedical Research, University of Victoria, Canada.
⁴ Center for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Canada.
⁵ Institute of Cardiovascular Sciences, St-Boniface Hospital Albrechtsen Research Centre Winnipeg, Canada.
⁶ Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
⁷ Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
⁸ Department of Pharmacology & Therapeutics, Center for Research and Treatment of Atherosclerosis, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
⁹ Regenerative Medicine Program, Spinal Cord Research Centre, Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada.
¹⁰ Genome Sciences Centre, BC Cancer, Vancouver, Canada.
¹¹ Patient Advocate and Research Committee, Brain Tumour Foundation of Canada, Ottawa, Canada.
¹² Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
¹³ Biology of Breathing, Children Hospital Research Institute of Manitoba, Max Rady College of Medicine, Rady Faculty of Health Sciences, Winnipeg, Canada.
¹⁴ Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Iran.

PMID: 31545550
DOI: 10.1111/febs.15069

Abstract

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.

Keywords: 3D culture; bafilomycin A1; glioblastoma; pleotropic effect; prenylation.

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References

1. Alifieris C & Trafalis DT (2015) Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 152, 63-82.
1. Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C & Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 19, v1-v88.
1. Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD et al. (2018) Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184, 13-41.
1. Sharifzad F, Ghavami S, Verdi J, Mardpour S, Mollapour Sisakht M, Azizi Z, Taghikhani A, Los MJ, Fakharian E, Ebrahimi M et al. (2019) Glioblastoma cancer stem cell biology: Potential theranostic targets. Drug Resist Updat 42, 35-45.
1. Khosla D (2016) Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Ann Transl Med 4, 54.

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[1] Alifieris C & Trafalis DT (2015) Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 152, 63-82.

[2] Alifieris C & Trafalis DT (2015) Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Ther 152, 63-82.

[3] Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C & Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 19, v1-v88.

[4] Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C & Barnholtz-Sloan JS (2017) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 19, v1-v88.

[5] Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD et al. (2018) Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184, 13-41.

[6] Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD et al. (2018) Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 184, 13-41.

[7] Sharifzad F, Ghavami S, Verdi J, Mardpour S, Mollapour Sisakht M, Azizi Z, Taghikhani A, Los MJ, Fakharian E, Ebrahimi M et al. (2019) Glioblastoma cancer stem cell biology: Potential theranostic targets. Drug Resist Updat 42, 35-45.

[8] Sharifzad F, Ghavami S, Verdi J, Mardpour S, Mollapour Sisakht M, Azizi Z, Taghikhani A, Los MJ, Fakharian E, Ebrahimi M et al. (2019) Glioblastoma cancer stem cell biology: Potential theranostic targets. Drug Resist Updat 42, 35-45.

[9] Khosla D (2016) Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Ann Transl Med 4, 54.

[10] Khosla D (2016) Concurrent therapy to enhance radiotherapeutic outcomes in glioblastoma. Ann Transl Med 4, 54.

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

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

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