Abstract
Temozolomide (TMZ)-induced chemoresistance to human glioblastomas is a critical challenge now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), can kill human glioblastoma cells and suppresses glioblastoma growth. This study was further aimed to evaluate the effects of honokiol on human drug-resistant glioblastoma cells and the possible mechanisms. The results by data mining in the cancer genome atlas (TCGA) database and immunohistochemistry displayed that expression of caspase-9 mRNA and protein in human glioblastomas was induced. Human TMZ-resistant U87-MG-R9 glioblastoma cells were selected and prepared from human drug-sensitive U87-MG cells. Compared to human drug-sensitive U87-MG cells, TMZ did not affect viability of U87-MG-R9 glioblastoma cells. Interestingly, treatment with honokiol suppressed proliferation and survival of human drug-resistant glioblastoma cells in concentration- and time-dependent manners. Compared to caspase-8 activation, honokiol chiefly increased activity of caspase-9 in U87-MG-R9 cells. Successively, levels of cleaved caspase-3 and activities of caspase-3 and caspase-6 in human TMZ-tolerant glioblastoma cells were augmented following honokiol administration. In parallel, honokiol triggered DNA fragmentation of U87-MG-R9 cells. Accordingly, treatment of human TMZ-resistant glioblastoma cells with honokiol induced cell apoptosis but did not affect cell necrosis. Fascinatingly, suppressing caspase-9 activity using its specific inhibitors repressed honokiol-induced caspase-6 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the major roles of caspase-9 in transducing honokiol-induced mitochondria-dependent apoptosis in human drug-resistant glioblastoma cells. Thus, honokiol may be clinically applied as a drug candidate for treatment of glioblastoma patients with chemoresistance.
Highlights
Glioblastomas are the most common and aggressive brain tumors [1]
Our study attractively suggested that honokiol has potential welfares for therapy of drug-resistant glioblastoma patients
We used the drug-tolerant glioblastoma cells as our experimental model to verify the beneficial effects of honokiol on suppressing cell proliferation and decreasing cell viability
Summary
Glioblastomas are the most common and aggressive brain tumors [1]. The patients with malignant glioblastomas usually have poor prognosis [2]. The median survival rate of glioblastoma patients is about 12 months. Temozolomide (TMZ) is the first-line chemotherapeutic drug for therapy of malignant glioblastomas [3]. TMZ may induce drug tolerance to high-grade glioblastomas, Molecules 2020, 25, 1450; doi:10.3390/molecules25061450 www.mdpi.com/journal/molecules. Molecules 2020, 25, 1450 especially in recurrent patients [4]. The chemoresistance is a serious issue for therapy of human glioblastomas. To build up a novel and effective strategy for treatment of human glioblastomas, it is very critical to discover new chemotherapeutic drugs that can overcome TMZ-induced drug tolerance
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