Journal
TUMOR BIOLOGY
Volume 39, Issue 5, Pages -Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1010428317692244
Keywords
Glioma; senescence; verapamil; carmustine; irradiation
Categories
Funding
- National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [2013M2A2A7042530]
- Next-Generation BioGreen 21 Program [PJ01107701]
- Korea University [K1608461]
- Kwanjeong Educational Foundation Domestic Scholarship
- Bonsol Kim Jong Han Educational Foundation
- National Research Foundation of Korea [2013M2A2A7042530] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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