Journal
AGING-US
Volume 13, Issue 5, Pages 6820-6831Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.202539
Keywords
nicardipine; apoptosis; autophagy; glioblastoma multiforme; glioma stem cells
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Funding
- Natural Science Foundation of Jiangsu Province [BK20201172]
- Clinical Special Disease Diagnosis and Treatment Technology in Suzhou [LCZX201807]
- Key project of Jiangsu Health Commission [ZDB2020016]
- Young Talent Development Plan of Changzhou Health Commission [2020-233-CZQM2020013]
- Changzhou Health and Family Planning Commission Youth Talent Science and Technology Project [WZ201811]
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The study found that nicardipine can enhance the toxic effect of temozolomide against GSCs, promote apoptosis of GSCs, and inhibit autophagy. These effects are related to the activation of mTOR, and the selective inhibition of mTOR by rapamycin can weaken the sensitization of nicardipine to temozolomide.
Glioblastoma multiforme (GBM) is the most invasive malignant central nervous system tumor with poor prognosis. Nicardipine, a dihydropyridine calcium channel antagonist, has been used as an adjuvant to enhance sensitivity to chemotherapeutic drugs. However, whether glioma stem cells (GSCs) can be sensitized to chemotherapy via combined treatment with temozolomide (TMZ) and nicardipine is unclear. In this study, surgical specimen derived GSCs SU4 and SU5 were applied to explore the sensitization effect of nicardipine on temozolomide against GSCs, and further explore the relevant molecular mechanisms. Our results showed that nicardipine can enhance the toxic effect of temozolomide against GSCs, promote apoptosis of GSCs, and inhibit autophagy of GSCs. The relevant mechanisms were related to activation of mTOR, and selective inhibition of mTOR by rapamycin could weaken the sensitization of nicardipine to temozolomide, which suggest that nicardipine can be applied as an adjuvant to inhibit autophagy in GSCs, and enhance apoptosis-promoting effect of temozolomide in GSCs as well. Nicardipine can inhibit autophagy by activating expression of mTOR, thus play tumor inhibition roles both in vitro and in vivo. Repurposing of nicardipine can help to improving therapeutic effect of TMZ against GBM, which deserves further clinical investigations.
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