Abstract
α-Hispanolol (α-H) is a labdane diterpenoid that has been shown to induce apoptosis in several human cancer cells. However, the effect of α-H in human glioblastoma cells has not been described. In the present work, we have investigated the effects of α-H on apoptosis, migration, and invasion of human glioblastoma cells with the aim of identifying the molecular targets underlying its mechanism of action. The results revealed that α-H showed significant cytotoxicity against human glioma cancer cell lines U87 and U373 in a concentration- and time-dependent manner. This effect was higher in U87 cells and linked to apoptosis, as revealed the increased percentage of sub-G1 population by cell cycle analysis and acquisition of typical features of apoptotic cell morphology. Apoptosis was also confirmed by significant presence of annexin V-positive cells and caspase activation. Pretreatment with caspase inhibitors diminishes the activities of caspase 8, 9, and 3 and maintains the percentage of viable glioblastoma cells, indicating that α-H induced cell apoptosis through both the extrinsic and the intrinsic pathways. Moreover, we also found that α-H downregulated the anti-apoptotic Bcl-2 and Bcl-xL proteins and activated the pro-apoptotic Bid and Bax proteins. On the other hand, α-H exhibited inhibitory effects on the migration and invasion of U87 cells in a concentration-dependent manner. Furthermore, additional experiments showed that α-H treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase MMP-2 and MMP-9 and increased the expression of TIMP-1 inhibitor, probably via p38MAPK regulation. Finally, xenograft assays confirmed the anti-glioma efficacy of α-H. Taken together, these findings suggest that α-H may exert anti-tumoral effects in vitro and in vivo through the inhibition of cell proliferation and invasion as well as by the induction of apoptosis in human glioblastoma cells. This research describes α-H as a new drug that may improve the therapeutic efficacy against glioblastoma tumors.
Highlights
Glioblastoma multiforme (GBM) is a rare disease with an incidence of 2–3 per 100,000 people
Hispanolone is a labdane diterpenoid isolated from Ballota hispanica, a plant species widely distributed in Spain (Savona et al, 1978)
We found that the hispanolone derivative α-H significantly inhibited cell growth and induced apoptosis in glioblastoma cells
Summary
Glioblastoma multiforme (GBM) is a rare disease with an incidence of 2–3 per 100,000 people. It is considered as one of the most malignant primary brain tumors in adults being associated with a bad prognosis. Resistance to apoptotic cell death, supported angiogenesis, and glioma cell invasion are believed to be the main mechanisms by which GBM shows resistance against conventional chemotherapy (Onishi et al, 2011). The exact procedures driving GBM pathogenesis are not well known. Further research is required to understand the underlying mechanisms of tumor progression in order to design more effective therapies
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