title: The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells.
abstract: Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na+/K+-ATPase. In addition to its known effects on cardiac muscle, recentin vitroandin vivoevidence 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 STATEMENTIn 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.
authors.affiliation: Department of Physiology and Pharmacology.|Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Garofalo
authors.affiliation: Department of Physiology and Pharmacology.|Center for Life Nanoscience-Istituto Italiano di Tecnologia.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Grimaldi
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chece
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.|Department of Molecular Medicine.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Porzia
authors.affiliation: Department of Experimental Medicine.
authors.forename: Stefania
authors.initials: S
authors.lastname: Morrone
authors.affiliation: Department of Experimental Medicine.
authors.forename: Fabrizio
authors.identifier: 0000-0002-7136-9839
authors.initials: F
authors.lastname: Mainiero
authors.affiliation: Department of Physiology and Pharmacology.|Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: D'Alessandro
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.|Department of Neurology and Psychiatry.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Esposito
authors.affiliation: Consiglio Nazionale delle Ricerche-Nanotec, Institute of Nanotechnology, Soft and Living Matter Laboratory, Department of Physics.
authors.forename: Barbara
authors.identifier: 0000-0001-8667-7255
authors.initials: B
authors.lastname: Cortese
authors.affiliation: Department of Physiology and Pharmacology.|Center for Life Nanoscience-Istituto Italiano di Tecnologia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Angelantonio
authors.affiliation: Department of Physiology and Pharmacology, Laboratory Affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy.
authors.forename: Flavia
authors.identifier: 0000-0002-7983-2955
authors.initials: F
authors.lastname: Trettel
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy, cristina.limatola@uniroma1.it.|Department of Physiology and Pharmacology, Laboratory Affiliated with Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy.
authors.forename: Cristina
authors.identifier: 0000-0001-7504-8197
authors.initials: C
authors.lastname: Limatola
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002298:Cardenolides / Q000494:pharmacology / Q000627:therapeutic use*; D002301:Cardiac Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D002298:Cardenolides; D002301:Cardiac Glycosides; C021065:oleandrin
keywords: BDNF; apoptosis; glioma; in vivo; invasion; oleandrin