Methods to Impair Hematologic Cancer Progenitor Cells and Compounds Related Thereto

Primitive or progenitor hematologic cancer cells have been implicated in the early stages and development of leukemia and malignant lymphoproliferative disorders, including acute myelogenous leukemia (AML), chronic myelogenous leuke mia (CML) and chronic lymphoid leukemia (CLL). Interleu kin-3 receptor alpha chain (IL-3Ra or CD123) is strongly expressed on progenitor hematologic cancer cells, but is vir tually undetectable on normal bone marrow cells. The present invention provides methods of impairing progenitor hemato logic cancer (e.g., leukemia and lymphomic) cells by selec tively targeting cells expressing CD123. These methods are useful in the detection and treatment of leukemias and malig nant lymphoproliferative disorders. Also provided are com pounds useful for selectively binding to CD123 and impairing progenitor hematologic cancer cells. These compounds may include cytotoxic moieties such as, for example, radioiso topes or chemotherapeutics

Use of Parthenolide Derivatives as Antileukemic and Cytotoxic Agents

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Use of Parthenolide Derivatives as Antileukemic and Cytotoxic Agents

To view this abstract, please download this patent

Use of Parthenolide Derivatives as Antileukemic and Cytotoxic Agents

To view this abstract, please download this patent

Caracterización fisicoquímica de películas formuladas a partir de proteína y mucílago de chía (Salvia hispanica, L.)

Una alternativa para el uso de plásticos que contribuyen al incremento de la contaminación ambiental, son los polímeros biodegradables producidos a partir de fuentes naturales como las semillas de chía. A partir de ella se pueden extraer componentes como la proteína y mucílago para la elaboración de películas. Las características fisicoquímicas de las películas influyen en gran medida en sus propiedades, es por ello que su conocimiento es relevante pues determinará sus potenciales aplicaciones

MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells

Triazole derivatives of melampomagnolide B (MMB) have been synthesized via click chemistry methodologies and screened against a panel of 60 human cancer cell lines. Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI50) values in the nanomolar range (GI50 = 0.02–0.99 μM). Lead compound 7h exhibited EC50 values of 400 nM and 700 nM, respectively, against two AML clinical specimens. Compound 7h was significantly more potent than parthenolide as an inhibitor of p65 phosphorylation in both hematological and solid tumor cell lines, indicating its ability to inhibit the NF-κB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-κB through inhibition of IKK-β mediated p65 phosphorylation and caused elevation of basal IκBα levels through inhibition of constitutive IκBα turnover and NF-κB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKβ subunit, leading to inhibition of IKKβ activation, and compromising phosphorylation of downstream targets of the NF-κB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKβ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKβ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development

Modulation of Cell Surface Protein Free Thiols: A Potential Novel Mechanism of Action of the Sesquiterpene Lactone Parthenolide

There has been much interest in targeting intracellular redox pathways as a therapeutic approach for cancer. Given recent data to suggest that the redox status of extracellular protein thiol groups (i.e. exofacial thiols) effects cell behavior, we hypothesized that redox active anti-cancer agents would modulate exofacial protein thiols.To test this hypothesis, we used the sesquiterpene lactone parthenolide, a known anti-cancer agent. Using flow cytometry, and western blotting to label free thiols with Alexa Fluor 633 C(5) maleimide dye and N-(biotinoyl)-N-(iodoacetyl) ethylendiamine (BIAM), respectively, we show that parthenolide decreases the level of free exofacial thiols on Granta mantle lymphoma cells. In addition, we used immuno-precipitation techniques to identify the central redox regulator thioredoxin, as one of the surface protein thiol targets modified by parthenolide. To examine the functional role of parthenolide induced surface protein thiol modification, we pretreated Granta cells with cell impermeable glutathione (GSH), prior to exposure to parthenolide, and showed that GSH pretreatment; (a) inhibited the interaction of parthenolide with exofacial thiols; (b) inhibited parthenolide mediated activation of JNK and inhibition of NFkappaB, two well established mechanisms of parthenolide activity and; (c) blocked the cytotoxic activity of parthenolide. That GSH had no effect on the parthenolide induced generation of intracellular reactive oxygen species supports the fact that GSH had no effect on intracellular redox. Together these data support the likelihood that GSH inhibits the effect of parthenolide on JNK, NFkappaB and cell death through its direct inhibition of parthenolide's modulation of exofacial thiols.Based on these data, we postulate that one component of parthenolide's anti-lymphoma activity derives from its ability to modify the redox state of critical exofacial thiols. Further, we propose that cancer cell exofacial thiols may be important and novel targets for therapy

Outbreak of Marburg hemorrhagic fever among miners in Kamwenge and Ibanda Districts, Uganda, 2007

Marburg hemorrhagic fever was detected among 4 miners in Ibanda District, Uganda, from June through September, 2007. Infection was likely acquired through exposure to bats or bat secretions in a mine in Kamwenge District, Uganda, and possibly human-to-human transmission between some patients. We describe the epidemiologic investigation and the health education response