Abstract
BackgroundTemozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms.MethodsTMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ.ResultsExposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells.ConclusionsTaken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.
Highlights
Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues
Exposure of human glioma cells to 40 μM honokiol for 24, 48, and 72 h respectively caused significant 18, 34 and 35% decreases in cell viability (Fig. 1b)
Despite TMZ being a firstline chemotherapeutic drug in standard concurrent chemoradiotherapy for glioma patients, drug resistance is Conclusions In summary, this study determined that the Lethal concentration 50% (LC50) of honokiol to human U87-MG glioma cells was 63.8 μM
Summary
Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. According to the grading system of the World Health Organization, gliomas are classed into low-grade pilocytic astrocytomas and diffuse fibrillary astrocytomas with better prognoses (grades I and II) as well as high-grade anaplastic astrocytoma and glioblastoma multiforme (GBM) with worse prognoses (grades III and IV). Among these glioma types, GBMs are most lethal brain tumors [2, 3]. Malignant gliomas remain a challenge in the face of optimal treatment that includes surgery and chemotherapy
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