Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells

Journal of Neurochemistry
Caroline HappoldMichael Weller

Abstract

Temozolomide (TMZ) is an alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma. Clinical benefit is more prominent in patients with methylation of the O(6) -methyl-guanine DNA methyltransferase (MGMT) promoter. However, all patients eventually suffer from tumor progression because their tumors become resistant to TMZ. Here, we modeled acquired TMZ resistance in glioma cells in vitro to identify underlying molecular mechanisms. To this end, the glioma cell lines LNT-229, LN-308, and LN-18 were exposed repetitively to increasing concentrations of TMZ to induce a stable resistant phenotype (R) defined by clonogenic survival assays. The molecular mechanisms mediating acquired resistance were assessed by immunoblot, PCR, and flow cytometry. Rescue experiments were performed with siRNA-mediated candidate gene silencing. We found in LN-18 cells constitutively expressing MGMT a strong up-regulation of MGMT levels in TMZ-resistant cells. TMZ resistance in the MGMT-negative cell lines LNT-229 and LN-308 was not associated with de novo expression of MGMT. Instead, we found a down-regulation of several DNA mismatch-repair proteins in resistant LNT-229 cells. A TMZ-resistant phenotype was also achieved b...Continue Reading

References

Mar 18, 1994·Science·N PapadopoulosM D Adams
Jul 1, 1996·Journal of Neuropathology and Experimental Neurology·J ReifenbergerG Reifenberger
Jul 16, 1997·Journal of the National Cancer Institute·C Gomez-ManzanoW K Yung
Aug 1, 1997·Molecular and Cellular Biology·V V OgryzkoB H Howard
Nov 24, 1999·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·L A HammondE K Rowinsky
Nov 9, 2000·The New England Journal of Medicine·M EstellerJ G Herman
Oct 16, 2004·Journal of Neurosurgery·Philipp RelleckeJuergen Schlegel
Mar 11, 2005·The New England Journal of Medicine·Roger StuppUNKNOWN National Cancer Institute of Canada Clinical Trials Group
Mar 11, 2005·The New England Journal of Medicine·Monika E HegiRoger Stupp
Feb 24, 2006·Journal of Molecular Biology·Stephen L GasiorPrescott L Deininger
May 4, 2006·Cancer Cell International·S Mehdi BelgnaouiAbdelali Haoudi
Aug 5, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jill A MaxwellHenry S Friedman
Jan 1, 2009·Biochemical and Biophysical Research Communications·Roberto PapaitElena Cattaneo
Jul 9, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Stephen YipDavid N Louis
Oct 29, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jörg FelsbergMichael C Sabel
Dec 10, 2009·Nature Reviews. Neurology·Michael WellerMonika E Hegi
Mar 23, 2011·International Journal of Cancer. Journal International Du Cancer·Jörg FelsbergUNKNOWN German Glioma Network

❮ Previous
Next ❯

Citations

Aug 2, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Brian P Sorrentino
Jul 12, 2014·Pharmaceuticals·Catherine L Moody, Richard T Wheelhouse
Oct 22, 2015·IUBMB Life·Cheng-Yi ChangChun-Jung Chen
Nov 8, 2012·Clinical & Developmental Immunology·Sadhak SenguptaPrakash Sampath
May 9, 2015·Future Oncology·Maira ZorzanCarla Mucignat-Caretta
Mar 17, 2015·Mutation Research·Aleksei StepanenkoVadym Kavsan
May 10, 2016·Cancer Cell International·Aleksei A StepanenkoVladimir V Dmitrenko
Aug 27, 2015·PloS One·Anna-Maria BarciszewskaMirosława Z Naskręt-Barciszewska
Sep 7, 2016·Expert Review of Anticancer Therapy·Tobias WeissPatrick Roth
Apr 21, 2017·Cell Death & Disease·Manuela SilginerPatrick Roth
Jun 16, 2017·Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al]·Christoph StraubeStephanie E Combs
Apr 27, 2018·The Quarterly Journal of Nuclear Medicine and Molecular Imaging : Official Publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of Radiopharmaceutica·Alessia PellerinoRoberta Rudà
Mar 17, 2017·Neurology·Dorothee GramatzkiMichael Weller
Apr 15, 2017·Oncotarget·Kiran K VelpulaAndrew J Tsung
Jun 10, 2020·Biomedicines·Verena J HerbenerHannah Strobel
Sep 25, 2020·Chemical Society Reviews·Cécile MingardShana J Sturla
Aug 24, 2019·International Journal of Cancer. Journal International Du Cancer·Ilya V UlasovMaciej S Lesniak
Dec 15, 2018·International Journal of Cancer. Journal International Du Cancer·Emilie Le RhunMichael Weller

❮ Previous
Next ❯

Related Concepts

Related Feeds