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Front. Pharmacol. | doi: 10.3389/fphar.2019.00935

α-hispanolol induces apoptosis and suppresses migration and invasion of glioblastoma cells likely via downregulation of MMP-2/9 expression and p38MAPK attenuation

  • 1Carlos III Health Institute, Spain
  • 2Complutense University of Madrid, Spain

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 down-regulated 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, xenografts 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 which may improve the therapeutic efficacy against glioblastoma tumors.

Keywords: α-hispanolol, Apoptosis, Glioblastoma, Caspases, Migration, MMPs

Received: 22 Feb 2019; Accepted: 22 Jul 2019.

Edited by:

Muriel Cuendet, Université de Genève, Switzerland

Reviewed by:

William Chi-Shing Tai, Hong Kong Polytechnic University, Hong Kong
Takahiro Kodama, Osaka University, Japan  

Copyright: © 2019 Sánchez-Martín, Jiménez-García, Herranz, Luque, Acebo, De Las Heras and Hortelano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sonsoles Hortelano, Carlos III Health Institute, Madrid, Madrid, Spain,