Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response

Sabine Hombach-Klonisch; Maryam Mehrpour; Shahla Shojaei; Craig Harlos; Marshall Pitz; Ahmed Hamai; Krzysztof Siemianowicz; Wirginia Likus; Emilia Wiechec; Brian D Toyota; Reyhane Hoshyar; Amir Seyfoori; Zahra Sepehri; Sudharsana R Ande; Forough Khadem; Mohsen Akbari; Adrienne M Gorman; Afshin Samali; Thomas Klonisch; Saeid Ghavami

doi:10.1016/j.pharmthera.2017.10.017

Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response

Pharmacol Ther. 2018 Apr:184:13-41. doi: 10.1016/j.pharmthera.2017.10.017. Epub 2017 Nov 8.

Authors

Sabine Hombach-Klonisch¹, Maryam Mehrpour², Shahla Shojaei³, Craig Harlos⁴, Marshall Pitz⁴, Ahmed Hamai², Krzysztof Siemianowicz⁵, Wirginia Likus⁶, Emilia Wiechec⁷, Brian D Toyota⁸, Reyhane Hoshyar⁹, Amir Seyfoori¹⁰, Zahra Sepehri¹¹, Sudharsana R Ande¹², Forough Khadem¹³, Mohsen Akbari¹⁰, Adrienne M Gorman¹⁴, Afshin Samali¹⁴, Thomas Klonisch¹⁵, Saeid Ghavami¹⁶

Affiliations

¹ Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
² Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, F-75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, F-75012 Paris, France.
³ Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Science, Isfahan, Iran.
⁴ Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
⁵ Department of Biochemistry, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
⁶ Department of Anatomy, School of Health Sciences in Katowice, Medical University of Silesia, Katowice, Poland.
⁷ Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
⁸ Division of Neurosurgery, Department of Surgery, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
⁹ Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran; Department of Clinical Biochemistry, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
¹⁰ Laboratory for Innovation in Microengineering (LiME), Department of Mechanical Engineering, University of Victoria, Victoria, BC, Canada.
¹¹ Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Internal Medicine Department, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
¹² Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.
¹³ Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
¹⁴ Apoptosis Research Centre, National University of Ireland, Galway, Ireland; School of Natural Sciences, National University of Ireland, Galway, Ireland.
¹⁵ Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada. Electronic address: thomas.klonisch@umanitoba.ca.
¹⁶ Department of Human Anatomy & Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Health Policy Research Centre, Shiraz Medical University of Medical Science, Shiraz, Iran. Electronic address: saeid.ghavami@umanitoba.ca.

PMID: 29080702
DOI: 10.1016/j.pharmthera.2017.10.017

Abstract

Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.

Keywords: Alkylating drugs; Apoptosis; Autophagy; Bcl-2 family protein; Brain tumor; Cancer therapy; Cell death; DNA repair; Glioblastoma; Glioblastoma stem cells; Temozolomide; Unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Apoptosis / drug effects*
Autophagy / drug effects*
Brain Neoplasms / drug therapy*
Drug Resistance, Neoplasm / drug effects*
Glioblastoma / drug therapy*
Humans
Models, Biological
Neoplastic Stem Cells / drug effects
Temozolomide / pharmacology
Temozolomide / therapeutic use
Unfolded Protein Response / drug effects*

Substances

Temozolomide