Verapamil augments carmustine- and irradiation-induced senescence in glioma cells by reducing intracellular reactive oxygen species and calcium ion levels.
TLDR
The results indicate that verapamil may be a potent therapeutic sensitizer for increasing the effectiveness of glioblastoma treatment.Abstract:
Resistance to conventional therapies and frequent recurrence are the major obstacles to the treatment of high-grade gliomas, including glioblastoma. Thus, the development of new therapeutic strategies to overcome these obstacles is necessary to improve the treatment outcomes. In this study, we found that verapamil, a pan-adenosine triphosphate-binding cassette transporter and L-type voltage-dependent calcium channel inhibitor, sensitized U87MG glioma cells to carmustine- and irradiation-induced senescence. Furthermore, our results indicated that verapamil treatment, in combination with carmustine and irradiation, rendered U87MG glioma cells and several patient-derived glioma stem cells more sensitive to therapy-induced senescence than individual or dual-combination treatments. When investigating the underlying mechanism, we found that verapamil treatment markedly decreased intracellular reactive oxygen species and calcium ion levels. Reactive oxygen species reduction with N-acetylcysteine, a reactive oxygen species scavenger, rendered U87MG glioma cells more sensitive to carmustine and irradiation whereas the protein kinase C agonist, phorbol 12-myristate 13-acetate, mitigated the effects of carmustine and irradiation. Taken together, our results indicate that verapamil may be a potent therapeutic sensitizer for increasing the effectiveness of glioblastoma treatment.read more
Citations
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The somatic genomic landscape of glioblastoma
Cameron Brennan,Roel G.W. Verhaak,Aaron McKenna,Benito Campos,Houtan Noushmehr,Sofie R. Salama,Siyuan Zheng,Debyani Chakravarty,J. Zachary Sanborn,Samuel H. Berman,Rameen Beroukhim,Brady Bernard,Chang-Jiun Wu,Giannicola Genovese,Ilya Shmulevich,Jill S. Barnholtz-Sloan,Lihua Zou,Rahulsimham Vegesna,Sachet A. Shukla,Giovanni Ciriello,W. K. Yung,Wei Zhang,Carrie Sougnez,Tom Mikkelsen,Kenneth Aldape,Darell D. Bigner,Erwin G. Van Meir,Michael D. Prados,Andrew E. Sloan,Keith L. Black,Jennifer M. Eschbacher,Gaetano Finocchiaro,William A. Friedman,David W. Andrews,Abhijit Guha,Mary Iacocca,Brian P. O'Neil,Greg Foltz,Jerome Myers,Daniel J. Weisenberger,Robert Penny,Raju Kucherlapati,Charles M. Perou,D. Neil Hayes,Richard A. Gibbs,Marco A. Marra,Gordon B. Mills,Eric S. Lander,Paul T. Spellman,Richard K. Wilson,Chris Sander,John N. Weinstein,Matthew Meyerson,Stacey Gabriel,Peter W. Laird,David Haussler,Gad Getz,Lynda Chin +57 more
TL;DR: In this article, the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs) was described, including several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA.
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An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme-Role in Pathogenesis and Therapeutic Perspective.
TL;DR: Using an animal model, it was shown that autophagy is required for Glioblastoma multiforme development and TMZ is the key player in TMZ resistance in GBM.
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Cellular senescence in ionizing radiation (Review).
TL;DR: This review summarizes the understanding of CS in IR, which may be beneficial for providing new insight for improving the therapeutic outcomes of RT.
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Molecular Mechanisms of Drug Resistance in Glioblastoma.
TL;DR: In this paper, a review summarizes recent advances in understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance.
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The effect of Verapamil on ischaemia/reperfusion injury in mouse ovarian tissue transplantation.
Maryam Saber,Hussein Eimani,Hussein Eimani,Malek Soleimani Mehranjani,Abdolhossein Shahverdi,Hamid Reza Momeni,Rouhollah Fathi,Somayeh Tavana +7 more
TL;DR: The results showed that verapamil treatment significantly preserved primordial follicular reserve and reduced the number of degenerated follicles compared to the transplanted group (P < 0.05).
References
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Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
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