Dimethylamino parthenolide clinical trials

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All authors read and approved the final manuscript. You can also search for this author in PubMed Google Scholar. Correspondence to Kodappully Sivaraman Siveen. Reprints and Permissions. The hydrophilic nature of the —COOH groups on the surface of fGn is responsible for the uniform dispersion of fGn in the cell culture medium, creating more contact with the cells without causing high cytotoxicity.

Nevertheless, pristine graphene induces a greater cytotoxic effect, as it has a tendency to accumulate on the cellular membrane, producing high levels of oxidative stress at the cellular level, as previously reported in the literature. The concentrations specific cytotoxicity of Gn and fGn. The WST-1 assay was used to determine the cytotoxicity of the carbon nanomaterials on Panc-1 cells. Data represent the mitochondrial dehydrogenase activity of Panc-1 cells after 24 h incubation with increasing concentrations of either Gn or fGn as a percentage of activity in untreated cells.

It is possible that the increased cytotoxicity exhibited by the PTL-fGn treatment was the result of higher intracellular concentrations of PTL being delivered to the Panc-1 cells compared to PTL treatment, alone. In the preparation of graphene and PTL-fGn mixtures, there is the possibility of a hydrophobic interaction between PTL and fGn, leading to graphene-mediated active delivery.

However, at the same time, the well-dispersed fGn particles are also able to promote enhanced cellular endocytosis and phagocytosis processes, 37 resulting in increased cellular uptake of free drug molecules surrounding the cells, which were otherwise incapable of internalization. PTL and DMAPT analogs perturb glutathione homeostasis by a multifactorial mechanism, including inhibition of the key glutathione metabolic enzymes glutamyl-cysteine ligase and glutathione peroxidase, leading to direct depletion of glutathione.

In the streptavidin pull-down assay, biotinylated parthenolide interacts with several proteins in AML cells that are all relevant to glutathione function and modulation of ROS. These studies clearly show that, primitive leukemia cells are uniquely sensitive to agents that target glutathione metabolism, resulting in significant increases in ROS and a subsequent increase in lethal double strand DNA breaks.

The concentrations specific cytotoxicity of Gn and fGn was determined by performing the WST-1 assay on Panc-1 cells after 24 h incubations. Reactive oxygen species ROS are chemically reactive molecules containing oxygen. Examples include superoxide radicle, hydroxyl radicle which results from exposure to ionizing radiation , and peroxide, as well as organic hydroperoxides such as lipid peroxides.

ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, if ROS levels are allowed to increase dramatically, this may result in significant damage to cell structures. The permeable DCFH-DA dye molecules travel across the cell membrane and are hydrolyzed by cellular esterases to form non-fluorescent 2',7'-dichlorodihydrofluorescein DCFH , which remains inside the cells.

No increase in ROS concentration was seen when cells were treated with fGn, alone. Maintenance of the intracellular redox system is critical for the survival of a cell.

This can be disturbed by enhanced production of intracellular reactive oxygen species ROS or a deficiency in the intracellular ROS buffering system, leading to the generation of oxidative stress. A number of anticancer drugs induce apoptosis by disrupting the redox system through inactivation of the thiol buffer system and by generation of intracellular ROS.

A ROS generation. B Caspase activation. MMP is indicative of mitochondrial integrity and overall cellular health. Depolarization of mitochondrial membranes or disruption of active mitochondria is an indication of early apoptosis. JC-1 dye is a cationic, lipophilic cell membrane permeable dye that forms a red fluorescent aggregate inside the mitochondrial matrix in healthy cells due to the presence of the inner mitochondrial membrane electrochemical potential gradient.

Depolarization of the mitochondrial membrane causes the transition pores to opens preventing accumulation of the dye in the mitochondrial matrix. As a result, the dye is seen as its green JC-1 monomer form in the cytoplasm. Untreated cells and cells treated with only fGn were included as controls.

JC-1 : Red fluorescent JC-1 aggregate forms inside the mitochondrial matrix of cells with healthy mitochondria. Depolarization of the mitochondrial membrane is indicated by the presence of green JC-1 monomer in the cytoplasm. Caspase : Healthy cells are unstained not visible.

Cells with active caspases stain green. The inset with arrows shows the apoptotic cells at higher magnification. Cells stained with both dyes will appear yellow.

The PTL-mediated ROS generation, like that observed above, has been shown to have a significant effect on mitochondrial health. ROS plays a critical role when it comes to signaling in cancer cells. It has been shown that over-production of ROS leads to apoptosis. This could then lead to the separation of Bax and Bcl proteins and the eventual release of cytochrome c into the cytoplasm. To provide information on and compare the apoptotic process induced by PTL and PTL-fGn in Panc-1 cells, cell permeable carboxy-fluorescein labeled fluoromethyl ketone FMK -peptide caspase inhibitors, which can bind covalently to active caspases caspase-1, -2, -3, -4, -5, -6, -7, -8, and -9 fluorescently labeling them in situ, were used.

The fluorescence of caspase positive cells can be quantified using a fluorescence plate reader Figure 7b and visualized using fluorescence microscopy Figure 8. Once again, this indicates that the cytotoxicity of PTL is significantly enhanced by fGn delivery.

The fluorescence microscopy images revealed similar results, as evidenced by the higher levels of green fluorescence, which were generated by most of the PTL-fGn treated cells Figure 8. The arrows in the inset of the micrograph showing PTL-fGn treatment indicate cellular membrane blebbing and disintegration of the nuclear membrane, the classic morphology of apoptotic cells. AO is a vital dye and can penetrate cell membranes; EB enters cells only upon membrane disintegration.

Healthy, living cells will appear uniformly green. Cells in the early stages of apoptosis will also stain green, but the nuclei will contain bright green spots which are a sign of chromatin condensation and nuclear fragmentation. Late apoptotic cells, which have lost membrane integrity, will also incorporate EB and stain orange. PTL-fGn treated cells showed an increase in apoptotic staining, as evidenced by the red and yellow staining, as well as the low cell numbers.

The TdT then catalyzes the addition of fluorescein-labeled deoxynucleotides that can be detected by microscopy. Annexin-V detects apoptotic changes in the lipid bilayers and binds to phosphatidyl serine moieties that translocate from the inner membrane to the outer membrane during early apoptosis.

PI penetrates and stains cells that have lost membrane integrity. This dual staining method is used to differentiate between apoptotic and necrotic cells. Also, very few cells were found to be only stained with PI, indicating that treatment with PTL causes apoptosis and that nanodelivery of the drug only increases this apoptotic effect. Craig T. Jordan, PhD Craig T. Jordan, PhD. Blood 22 : Cite Icon Cite. Abstract Poster Board II We have previously demonstrated that parthenolide PTL , a naturally occurring small molecule found in feverfew Chrysanthemum parthenium , induces apoptosis in primary acute myeloid leukemia AML cells, including the stem and progenitor cell compartment.

Add comment Close comment form modal. Submit a comment. Comment title. You have entered an invalid code. Submit Cancel. Thank you for submitting a comment on this article. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability.