RT Journal Article
SR Electronic
T1 The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3926
OP 3939
DO 10.1523/JNEUROSCI.2296-16.2017
VO 37
IS 14
A1 Stefano Garofalo
A1 Alfonso Grimaldi
A1 Giuseppina Chece
A1 Alessandra Porzia
A1 Stefania Morrone
A1 Fabrizio Mainiero
A1 Giuseppina D'Alessandro
A1 Vincenzo Esposito
A1 Barbara Cortese
A1 Silvia Di Angelantonio
A1 Flavia Trettel
A1 Cristina Limatola
YR 2017
UL http://www.jneurosci.org/content/37/14/3926.abstract
AB Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na+/K+-ATPase. In addition to its known effects on cardiac muscle, recent in vitro and in vivo evidence highlighted its potential for anticancer properties. Here, we evaluated for the first time the effect of oleandrin on brain tumors. To this aim, mice were transplanted with human or murine glioma and analyzed for tumor progression upon oleandrin treatment. In both systems, oleandrin impaired glioma development, reduced tumor size, and inhibited cell proliferation. We demonstrated that oleandrin does the following: (1) enhances the brain-derived neurotrophic factor (BDNF) level in the brain; (2) reduces both microglia/macrophage infiltration and CD68 immunoreactivity in the tumor mass; (3) decreases astrogliosis in peritumoral area; and (4) reduces glioma cell infiltration in healthy parenchyma. In BDNF-deficient mice (bdnftm1Jae/J) and in glioma cells silenced for TrkB receptor expression, oleandrin was not effective, indicating a crucial role for BDNF in oleandrin's protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide-treated mice. These results encourage the development of oleandrin as possible coadjuvant agent in clinical trials of glioma treatment.SIGNIFICANCE STATEMENT In this work, we paved the road for a new therapeutic approach for the treatment of brain tumors, demonstrating the potential of using the cardioactive glycoside oleandrin as a coadjuvant drug to standard chemotherapeutics such as temozolomide. In murine models of glioma, we demonstrated that oleandrin significantly increased mouse survival and reduced tumor growth both directly on tumor cells and indirectly by promoting an antitumor brain microenvironment with a key protective role played by the neurotrophin brain-derived neurotrophic factor.