ABSTRACT
Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane-binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.
Subject(s)
Anthozoa/chemistry , Antineoplastic Agents/chemistry , Biological Products/chemistry , Complex Mixtures/chemistry , Diterpenes/chemistry , Small Molecule Libraries/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Cell Line, Tumor , Complex Mixtures/pharmacology , Computational Biology , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Halogenation , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
Alzheimer's disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aß peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.
Subject(s)
Alzheimer Disease/metabolism , Bexarotene/pharmacology , Myelin Sheath/metabolism , Neuroprotective Agents/pharmacology , Oligodendroglia/drug effects , Retinoid X Receptors/agonists , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Cell Proliferation , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Female , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Oligodendroglia/metabolism , Oligodendroglia/physiology , Presenilin-1/genetics , tau Proteins/geneticsABSTRACT
The Caribbean soft coral Erythropodium caribaeorum is a rich source of erythrolides-chlorinated briarane diterpenoids. These compounds have an ecological role as feeding deterrents, with a wide variation in their composition depending on the location where the sample is collected. In Colombia, this soft coral can be found at different locations in the Caribbean Sea including Santa Marta, Islas del Rosario, and Providencia-three environmentally different coral reef areas in the south and southwest Caribbean Sea. In order to evaluate differences in erythrolide composition, the metabolic profiles of samples from each of these locations were analyzed by HPLC-MS. Principal component analysis showed changes in the diterpene composition according to the sample origin. Diterpenes from samples collected at each location were isolated to describe the three chemotypes. The chemotype from Santa Marta was highly diverse, with the new erythrolides W and X together with eight known erythrolides. The sample from Islas del Rosario showed a low diversity chemotype constituted by high amounts of erythrolide A and B. The chemotype from Providencia showed low chemical diversity with only two main compounds-erythrolide V and R. Evaluation of cytotoxic activity against the human cancer cell lines PC-3, MCF7, and A549 showed erythrolides A and B as the more active compounds with IC50 values in the range from 2.45 to 30 µM.
Subject(s)
Anthozoa/chemistry , Metabolome , Animals , Anthozoa/metabolism , Caribbean Region , Colombia , Coral Reefs , Diterpenes/chemistry , HumansABSTRACT
The vascular hypothesis of Alzheimer's disease postulates that disruption of the brain microvasculature is important for the accumulation of amyloid beta and increased neuroinflammation. Liver X Receptor agonist, GW3965, has been demonstrated to successfully modulate neuroinflammation and lipid metabolism in murine models of AD. This is partially due to increased expression of ApoE levels and increased mobility of endothelial progenitor cells. This paper analyzes changes in the neurovascular unit and in astrocytes and microglia markers following oral administration of GW3965 in a very old triple transgenic AD mice (3xTg-AD mice). We found that astrogliosis, but not activation of microglia, decreased in very old (24 months) 3xTg-AD mice treated with GW965. In addition, GW3965 increased LRP1 levels in neuron-like cells and partially restored microvascular morphology by decreasing tortuosity and increasing length as shown by Lectin immunostaining. Interestingly, these changes were associated with decreased Aß in blood vessels. In conclusion, short-term treatment of 3xTg-AD mice with GW3965 restored microvascular architecture which may be important in the cognitive improvement previously shown.
Subject(s)
Alzheimer Disease/metabolism , Hippocampus/blood supply , Hippocampus/metabolism , Liver X Receptors/agonists , Microvessels/metabolism , Aging , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Astrocytes/metabolism , Benzoates/pharmacology , Benzylamines/pharmacology , Biomarkers/metabolism , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Liver X Receptors/metabolism , Mice , Mice, Transgenic , Microglia/metabolism , Microvessels/drug effects , Microvessels/pathology , Neurons/metabolismABSTRACT
Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.