PMID- 28292827
OWN - NLM
STAT- MEDLINE
DCOM- 20170727
LR  - 20200225
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 37
IP  - 14
DP  - 2017 Apr 5
TI  - The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on 
      Tumor Cells.
PG  - 3926-3939
LID - 10.1523/JNEUROSCI.2296-16.2017 [doi]
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.
CI  - Copyright (c) 2017 the authors 0270-6474/17/373926-14$15.00/0.
FAU - Garofalo, Stefano
AU  - Garofalo S
AD  - Department of Physiology and Pharmacology.
AD  - Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, 
      Italy.
FAU - Grimaldi, Alfonso
AU  - Grimaldi A
AD  - Department of Physiology and Pharmacology.
AD  - Center for Life Nanoscience-Istituto Italiano di Tecnologia.
FAU - Chece, Giuseppina
AU  - Chece G
AD  - Department of Physiology and Pharmacology.
FAU - Porzia, Alessandra
AU  - Porzia A
AD  - Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, 
      Italy.
AD  - Department of Molecular Medicine.
FAU - Morrone, Stefania
AU  - Morrone S
AD  - Department of Experimental Medicine.
FAU - Mainiero, Fabrizio
AU  - Mainiero F
AUID- ORCID: 0000-0002-7136-9839
AD  - Department of Experimental Medicine.
FAU - D'Alessandro, Giuseppina
AU  - D'Alessandro G
AD  - Department of Physiology and Pharmacology.
AD  - Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, 
      Italy.
FAU - Esposito, Vincenzo
AU  - Esposito V
AD  - Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, 
      Italy.
AD  - Department of Neurology and Psychiatry.
FAU - Cortese, Barbara
AU  - Cortese B
AUID- ORCID: 0000-0001-8667-7255
AD  - Consiglio Nazionale delle Ricerche-Nanotec, Institute of Nanotechnology, Soft and 
      Living Matter Laboratory, Department of Physics.
FAU - Di Angelantonio, Silvia
AU  - Di Angelantonio S
AD  - Department of Physiology and Pharmacology.
AD  - Center for Life Nanoscience-Istituto Italiano di Tecnologia.
FAU - Trettel, Flavia
AU  - Trettel F
AUID- ORCID: 0000-0002-7983-2955
AD  - Department of Physiology and Pharmacology, Laboratory Affiliated with Istituto 
      Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, 
      Italy.
FAU - Limatola, Cristina
AU  - Limatola C
AUID- ORCID: 0000-0001-7504-8197
AD  - Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, 
      Italy, cristina.limatola@uniroma1.it.
AD  - Department of Physiology and Pharmacology, Laboratory Affiliated with Istituto 
      Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, 
      Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170314
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Cardenolides)
RN  - 0 (Cardiac Glycosides)
RN  - II95UDU7I4 (oleandrin)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - Cardenolides/pharmacology/*therapeutic use
MH  - Cardiac Glycosides/pharmacology/*therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects/physiology
MH  - Glioma/*drug therapy/pathology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, SCID
MH  - Mice, Transgenic
MH  - Tumor Burden/*drug effects/physiology
MH  - Xenograft Model Antitumor Assays/methods
PMC - PMC6596714
OTO - NOTNLM
OT  - BDNF
OT  - apoptosis
OT  - glioma
OT  - in vivo
OT  - invasion
OT  - oleandrin
EDAT- 2017/03/16 06:00
MHDA- 2017/07/28 06:00
PMCR- 2017/10/05
CRDT- 2017/03/16 06:00
PHST- 2016/07/18 00:00 [received]
PHST- 2017/02/27 00:00 [revised]
PHST- 2017/02/27 00:00 [accepted]
PHST- 2017/03/16 06:00 [pubmed]
PHST- 2017/07/28 06:00 [medline]
PHST- 2017/03/16 06:00 [entrez]
PHST- 2017/10/05 00:00 [pmc-release]
AID - JNEUROSCI.2296-16.2017 [pii]
AID - 2296-16 [pii]
AID - 10.1523/JNEUROSCI.2296-16.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2017 Apr 5;37(14):3926-3939. doi: 10.1523/JNEUROSCI.2296-16.2017. 
      Epub 2017 Mar 14.