The glycoside oleandrin reduces glioma growth with direct and indirect effects on tumor cells.

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 potential for anticancer properties of this compound. In this paper 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 i) enhances brain-derived neurotrophic factor (BDNF) level in the brain; ii) reduces both microglia/macrophage (M/Mphi) infiltration and CD68 immunoreactivity in the tumor mass; iii) decreases astrogliosis in peritumoral area; and iv )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 protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide (TMZ) treated mice. Altogether these results encourage the development of oleandrin as possible co-adjuvant agent in clinical trials of glioma treatment.SIGNIFICANCE STATEMENTIn this work we paved the road for a new therapeutic approach for the treatment of brain tumor, demonstrating the potential of using the cardioactive glycoside oleandrin as co-adjuvant drug to standard chemotherapeutics such as temozolomide.In murine models of glioma, we demonstrated that oleandrin significantly increased mice survival and reduced tumor growth, both directly on tumor cells and indirectly by promoting an anti-tumor brain microenvironment with a key protective role played by the neurotrophin BDNF.