Monoamine oxidase B activity is increased in human gliomas

Gabilondo, Ane M.; Hostalot, Cristina; Garibi, J.; Meana, J. Javier; Callado, Luís F.

doi:10.1016/j.neuint.2007.05.015

Cited by 20 publications

(15 citation statements)

References 31 publications

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“…To determine whether the differential toxic effects of MP‐MUS on glioma cells and NHAs are caused by the difference in intracellular MAO‐B levels, we first measured the concentration of MAO‐B in both cells via measurement of fluorescence intensity of Alexa Fluor 488‐labeled anti‐MAO‐B antibody. The data presented in Figure 4 d suggest that NHAs expressed ≈5‐fold less MAO‐B than glioma cells, which is in good agreement with reported data 12. To further study the MAO‐B‐dependent toxicity of MP‐MUS, we exposed human primary glioma cells to selegiline prior to treatment with MP‐MUS at 210 μ M .…”

Section: Resultssupporting

confidence: 88%

“…By measuring MAO oxidation of phenylethylamine in the absence or presence of the MAO‐B‐specific inhibitor L ‐deprenyl (selegiline), MAO‐B activity was found to be significantly up‐regulated in glial tumors relative to control brain tissue or non‐glial brain tumors 12. Immuno‐histological studies in our research group have confirmed this observation (unpublished results).…”

Section: Introductionsupporting

confidence: 58%

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Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

et al. 2015

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Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ≥fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75 μM, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180 μM MP-MUS killed 90-95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis.

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Section: Resultssupporting

confidence: 88%

Section: Introductionsupporting

confidence: 58%

Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

et al. 2015

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“…Finally, certain cancers have been reported that MAO‐A mediates prostate tumorigenesis and cancer metastasis and that MAO‐B is elevated in human gliomas when compared with meningiomas or nontumoral tissue . These studies suggest that the quantification of MAO activity with PET may be useful in characterizing tumor biology and for tailoring cancer treatment to the biology of the tumor.…”

Section: Discussionmentioning

confidence: 91%

Monoamine oxidase: radiotracer chemistry and human studies

Fowler

Logan

Shumay

et al. 2015

Labelled Comp Radiopharmac

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Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serotonin, norepinephrine, and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson's disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 years since the first radiotracers were developed and the first positron emission tomography (PET) images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables that have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe the following: (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological, and psychiatric disorders; and (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers that are currently used and possible new applications.

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“…Human gliomas exhibit significant and selective increases in MAOB activity compared to other types of common brain tumors, such as meningiomas ( Callado et al, 2011 ), or non-tumor-bearing brain tissues ( Gabilondo et al, 2008 ). This characteristic presents a distinct opportunity for rational drug design using MAOB as a catalyst for converting a non-toxic pro-drug into a mature chemotherapeutic, as demonstrated here with MP-MUS.…”

Section: Discussionmentioning

confidence: 99%

“…MAOB is mainly expressed in glial astrocytes in humans and mice ( Ekblom et al, 1993 ) and oxidizes neuroactive amines, such as dopamine ( Wang and Edmondson, 2011 ). MAOB activity levels have been reported to be significantly higher in GBMs, low-grade astrocytomas, and anaplastic astrocytomas compared to those of postmortem control brain (p < 0.01) ( Gabilondo et al, 2008 ) ( Callado et al, 2011 ). Glioma cells have 5–10 times fewer mitochondria than those of normal human astrocytes ( Wolf et al, 2011 ) and far less complex I–IV ( Kiebish et al, 2009 ).…”

Section: Introductionmentioning

confidence: 98%

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

Sharpe¹,

Livingston²,

Gist³

et al. 2015

EBioMedicine

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The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

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Monoamine oxidase B activity is increased in human gliomas

Cited by 20 publications

References 31 publications

Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

Monoamine oxidase: radiotracer chemistry and human studies

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

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