Review of PP2A Tumor Biology and Anti-Tumor Effects of PP2A Inhibitor LB100 in the Nervous System

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system and dysregulation of its cellular functions are associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radio-sensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Further, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

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Review of PP2A Tumor Biology and Antitumor Effects of PP2A Inhibitor LB100 in the Nervous System

Cancers ◽

10.3390/cancers13123087 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3087

Author(s):

Jean-Paul Bryant ◽

Adam Levy ◽

John Heiss ◽

Yeshavanth Kumar Banasavadi-Siddegowda

Keyword(s):

Nervous System ◽

Therapeutic Potential ◽

Tumor Biology ◽

Current Evidence ◽

Inhibitory Effects ◽

Cellular Functions ◽

Antitumor Effects ◽

Phosphatase 2A ◽

Pp2a Inhibitor

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system, and dysregulation of its cellular functions is associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radiosensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Furthermore, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

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Role of the Autonomic Nervous System in the Tumor Micro-Environment and its Therapeutic Potential

Current Pharmaceutical Design ◽

10.2174/13816128226661610251529420 ◽

2017 ◽

Author(s):

Zhifang Xu ◽

Yi Guo

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Therapeutic Potential ◽

Autonomic Nervous

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The Role of the JC Virus in Central Nervous System Tumorigenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21176236 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6236

Author(s):

Nicholas Ahye ◽

Anna Bellizzi ◽

Dana May ◽

Hassen S. Wollebo

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Tumor ◽

Animal Models ◽

Causative Agent ◽

Jc Virus ◽

Tumor Formation ◽

Current Evidence ◽

Merkel Cell

Cancer is the second leading cause of mortality worldwide. The study of DNA tumor-inducing viruses and their oncoproteins as a causative agent in cancer initiation and tumor progression has greatly enhanced our understanding of cancer cell biology. The initiation of oncogenesis is a complex process. Specific gene mutations cause functional changes in the cell that ultimately result in the inability to regulate cell differentiation and proliferation effectively. The human neurotropic Polyomavirus JC (JCV) belongs to the family Polyomaviridae and it is the causative agent of progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease in an immunosuppressed state. Sero-epidemiological studies have indicated JCV infection is prevalent in the population (85%) and that initial infection usually occurs during childhood. The JC virus has small circular, double-stranded DNA that includes coding sequences for viral early and late proteins. Persistence of the virus in the brain and other tissues, as well as its potential to transform cells, has made it a subject of study for its role in brain tumor development. Earlier observation of malignant astrocytes and oligodendrocytes in PML, as well as glioblastoma formation in non-human primates inoculated with JCV, led to the hypothesis that JCV plays a role in central nervous system (CNS) tumorigenesis. Some studies have reported the presence of both JC viral DNA and its proteins in several primary brain tumor specimens. The discovery of new Polyomaviruses such as the Merkel cell Polyomavirus, which is associated with Merkel cell carcinomas in humans, ignited our interest in the role of the JC virus in CNS tumors. The current evidence known about JCV and its effects, which are sufficient to produce tumors in animal models, suggest it can be a causative factor in central nervous system tumorigenesis. However, there is no clear association between JCV presence in CNS and its ability to initiate CNS cancer and tumor formation in humans. In this review, we will discuss the correlation between JCV and tumorigenesis of CNS in animal models, and we will give an overview of the current evidence for the JC virus’s role in brain tumor formation.

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Role and Therapeutic Potential of Melatonin in the Central Nervous System and Cancers

Cancers ◽

10.3390/cancers12061567 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1567

Author(s):

Sangiliyandi Gurunathan ◽

Min-Hee Kang ◽

Jin-Hoi Kim

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Circadian Rhythms ◽

Pineal Gland ◽

Therapeutic Potential ◽

Neurological Diseases ◽

Dark Phase ◽

Anti Inflammatory ◽

The Impact

Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.

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Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Nutrients ◽

10.3390/nu12123631 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3631

Author(s):

Ketaki Gadkari ◽

Urvi Kolhatkar ◽

Rutu Hemani ◽

Gisella Campanelli ◽

Qing Cai ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Progression ◽

Cancer Progression ◽

Therapeutic Potential ◽

Inhibitory Effects ◽

Antitumor Effects ◽

Anticancer Effects ◽

Potent Inhibition ◽

Avian Erythroblastosis Virus

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

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Neutrophils in cystic fibrosis

Biological Chemistry ◽

10.1515/hsz-2015-0271 ◽

2016 ◽

Vol 397 (6) ◽

pp. 485-496 ◽

Cited By ~ 32

Author(s):

Julie Laval ◽

Anjali Ralhan ◽

Dominik Hartl

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Structural Damage ◽

Fungal Pathogens ◽

Therapeutic Potential ◽

Inflammatory Cells ◽

Current Evidence ◽

Infection And Inflammation ◽

Shed Light

Abstract Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

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Recent progress in research on molecular mechanisms of autophagy in the heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00711.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. H259-H268 ◽

Cited By ~ 21

Author(s):

Yasuhiro Maejima ◽

Yun Chen ◽

Mitsuaki Isobe ◽

Åsa B. Gustafsson ◽

Richard N. Kitsis ◽

...

Keyword(s):

Heart Disease ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Degradation Process ◽

Structure And Function ◽

Cellular Functions ◽

Evolutionarily Conserved ◽

And Function ◽

Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

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Role of the glucose-dependent insulinotropic polypeptide and its receptor in the central nervous system: therapeutic potential in neurological diseases

Behavioural Pharmacology ◽

10.1097/fbp.0b013e32833c8544 ◽

2010 ◽

Vol 21 (5-6) ◽

pp. 394-408 ◽

Cited By ~ 39

Author(s):

Cláudia P. Figueiredo ◽

Fabrício A. Pamplona ◽

Tânia L. Mazzuco ◽

Aderbal S. Aguiar ◽

Roger Walz ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Therapeutic Potential ◽

Neurological Diseases ◽

The Central Nervous System

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Tuning the regulator: Phosphorylation of KCC2 at two specific sites is critical for neurodevelopment

Science Signaling ◽

10.1126/scisignal.aay8960 ◽

2019 ◽

Vol 12 (603) ◽

pp. eaay8960 ◽

Cited By ~ 1

Author(s):

Gerald W. Zamponi

Keyword(s):

Nervous System ◽

Molecular Switch ◽

Inhibitory Effects

The K+/Cl− cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous system pathology.

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