Dataset Information

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, 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.

SUBMITTER: Garofalo S

PROVIDER: S-EPMC6596714 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells.

Garofalo Stefano S Grimaldi Alfonso A Chece Giuseppina G Porzia Alessandra A Morrone Stefania S Mainiero Fabrizio F D'Alessandro Giuseppina G Esposito Vincenzo V Cortese Barbara B Di Angelantonio Silvia S Trettel Flavia F Limatola Cristina C

The Journal of neuroscience : the official journal of the Society for Neuroscience 20170314 14

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 ...[more]

PMID: 28292827

Similar Datasets

Project description:BACKGROUND:Monoamine oxidase (MAO) A catalyzes oxidative deamination of monoamine neurotransmitters and dietary amines and regulates brain development and functions. Recently, we showed that MAO A mediates the progression and migration of glioma and MAO A inhibitors reduce glioma cell growth. Glioblastoma (GBM) is a common and most malignant brain tumor which is difficult to treat. Temozolomide (TMZ) is the current standard chemotherapy for glioma, but tumors usually become resistant and recur. So far, no effective therapy for TMZ-resistant glioma is available. Natural plant antimicrobial solution (PAMs) is a Chinese herbal medicine which has been used for decades without toxicity and has multiple medical functions including anti- inflammatory effects. Here, we report the effects of PAMs on glioblastoma growth. METHODS:The growth of TMZ -sensitive (U251S),-resistant (U251R) human glioma cells, and mouse glioma cell line GL-26 were assessed by MTS colorimetric assay, colony formation, and cell migration assays. Male C57BL/6 mice were implanted subcutaneously or intracranial with luciferase-positive mouse glioma GL-26 cells and treated with vehicle; MAO A inhibitor clorgyline (10?mg/kg); TMZ (1?mg/kg); PAMs (48?mg/kg) alone or in combination with TMZ (1?mg/kg) for 14?days. At the end of the treatment, mice were sacrificed, MAO A catalytic activity in tumors was measured, and tumor sizes were determined by imaging and weight. RESULTS:These results show that PAMs inhibits MAO A catalytic activity in all three glioma cell lines studied U251S, U251R, and GL-26. PAMs reduced glioma growth and has greater effects in combination with low dose of TMZ than PAMS or TMZ alone in all three cell lines as shown by MTS, colony formation, and cell migration assays. Using the subcutaneous or intracranial GL-26 glioma mouse model, PAMs reduced the tumor growth and MAO A activity, similar to the MAO A inhibitor clorgyline. Combining PAMs with non-toxic dose TMZ increased survival to a greater extent than those of PAMs or TMZ alone. CONCLUSIONS:This is the first study which suggests that PAMs alone or co-administration with low doses of TMZ may be a potential adjuvant to reduce the toxicity of TMZ and to abrogate drug resistance for the effective treatment of glioma.

Project description:BackgroundFamily members resemble each other in their propensity for aggression. In twin studies, approximately 50% of the variance in aggression can be explained by genetic influences. However, if there are genotype-environment correlation mechanisms, such as environmental manifestations of parental and sibling genotypes, genetic influences may partly reflect environmental influences. In this study, we investigated the importance of indirect polygenic score (PGS) effects on aggression.MethodsWe modeled the effect of PGSs based on 3 genome-wide association studies: early-life aggression, educational attainment, and attention-deficit/hyperactivity disorder (ADHD). The associations with aggression were tested in a within- and between-family design (37,796 measures from 7740 individuals, ages 3-86 years [mean = 14.20 years, SE = 12.03], from 3107 families, 55% female) and in a transmitted/nontransmitted PGS design (42,649 measures from 6653 individuals, ages 3-61 years [mean = 11.81 years, SE = 8.68], from 3024 families, 55% female). All participants are enrolled in the Netherlands Twin Register.ResultsWe found no evidence for contributions of indirect PGS effects on aggression in either a within- and between-family design or a transmitted/nontransmitted PGS design. Results indicate significant direct effects on aggression for the PGSs based on early-life aggression, educational attainment, and ADHD, although explained variance was low (within- and between-family: early-life aggression R2 = 0.3%, early-life ADHD R2 = 0.6%, educational attainment R2 = 0.7%; transmitted/nontransmitted PGSs: early-life aggression R2 = 0.2%, early-life ADHD R2 = 0.9%, educational attainment R2 = 0.5%).ConclusionsPGSs included in the current study had a direct (but no indirect) effect on aggression, consistent with results of previous twin and family studies. Further research involving other PGSs for aggression and related phenotypes is needed to determine whether this conclusion generalizes to overall genetic influences on aggression.

Dataset Information

The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells.

Publications

The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets