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MAO inhibitors and their conjugates as therapeutics for the treatment of brain cancer

An inhibitor, brain cancer technology, applied in medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., can solve problems such as limited treatment options

Inactive Publication Date: 2016-11-16
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Then treatment options are very limited

Method used

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  • MAO inhibitors and their conjugates as therapeutics for the treatment of brain cancer
  • MAO inhibitors and their conjugates as therapeutics for the treatment of brain cancer
  • MAO inhibitors and their conjugates as therapeutics for the treatment of brain cancer

Examples

Experimental program
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Effect test

Embodiment 1

[0172] Expression of MAO A in human glioma tissues and cells

[0173] The results showed that there was prominent staining of MAO A in GBM tissues, while no detectable staining was observed in non-tumor brain tissues ( figure 2 A). Based on morphology, the staining of GBM appeared to be associated with tumor cells. As shown by immunostaining ( figure 2 B), Both sensitive (U251S) and resistant (U251R) human glioma cells express MAO A. Then using serotonin as a substrate ( figure 2 C) These glioma cell cultures were analyzed for MAO activity (5) and were shown to express MAO A catalytic activity; in contrast, normal control astrocytes exhibited no detectable MAO A activity.

[0174] MAO A activity was also measured in the mouse glioma cell line GL26; these tumor cells showed high levels of MAO A activity. Based on this information, GL26 cells were chosen to evaluate the inhibitory effect of different MAO inhibitors. Clogiline and phenelzine inhibit MAO A activity with 1...

Embodiment II

[0176] MAO A inhibitors clogiline and NMI (near-infrared dye-conjugated MAO inhibitor) reduce proliferation, viability and migration of TMZ-sensitive and resistant glioma cells

[0177] MAO A inhibitors target MAO A expression in both the central nervous system and peripheral tissues. To specifically target MAOA to brain cancer cells, the MAO inhibitor clogiline was conjugated to the near-infrared (NIR) tumor-specific dye MHI-148 to generate a novel drug NMI ( Figure 5 A), It accumulates preferentially in cancerous lesions. NMI has been based on figure 1 Synthesized by the steps shown in.

[0178]To evaluate the cellular uptake of NMI in human glioma cells, confocal microscopy was used. Image analysis of tumor cells treated with NMI (1 μM, 5 μM) showed significant dose-dependent uptake compared to vehicle. As determined by the mitochondria-specific dye MitoTracker Green ( Figure 5 B), The compound rapidly accumulates and localizes to mitochondria in U251R cells. Inhibi...

Embodiment III

[0185] Genetically modified MAO A knockout (MAO A KO) animals exhibit increased survival.

[0186] IHC was used to determine the expression of MAO A in human GBM tissues ( figure 2 B), In contrast less staining of MAO A in non-tumor brain. These results showed that the higher expression of MAO A in glioma cells and GBM tissues indicated that MAO A was involved in GBM progression.

[0187] To examine the in vivo effect of MAO A on tumor growth, tumor progression was analyzed in MAO A knockout mice (KO) in C57bl / 6 mice. Mouse glioma cells (GL26) derived from C57bl / 6 mice were used in these studies because these tumor cells showed high levels of MAO A activity ( figure 2 C). Tumor cells were luciferase-labeled and implanted intracranially in MAO AKO and WT C57bl / 6 mice; luciferase imaging was performed on day 10. The results showed a 75% reduction in tumor burden ( Figure 6 A and B), survival increased by 17.6% (3 days) ( Figure 6 C).

[0188] MAO A activity was determ...

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Abstract

A pharmaceutical composition and method for treating brain cancer are provided. The method includes administering to a patient in need thereof an effective amount of one or more compounds that include moclobemide, clorgyline, clorgyline's Near-infra-red dye Monoamine Oxidase Inhibitor (NMI), and MHI 148- clorgyline, and their salt thereof. The composition and method are particularly effective in reducing the size of glioblastomas that are temozolomide (TMZ) resistant.

Description

[0001] Statement Regarding Federally Funded Research and Development [0002] This invention was made with Government support under Contract No. R01-MH39085 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [0003] Cross References to Related Applications [0004] This application claims priority to US Provisional Application Serial No. 61 / 937,425, filed February 7, 2014, the contents of which are hereby incorporated by reference in their entirety. technical field [0005] The present invention relates generally to the inhibition of monoamine oxidase (MAO), and inhibitors thereof (MAOIs), in the treatment of brain cancer. Background technique [0006] Glioblastoma multiforme (GBM), the most aggressive form of primary brain tumor, has a median survival time of approximately 14 months (1). Current treatments include surgery, radiation therapy, and chemotherapy. The chemotherapeutic agent used in GBM treatment is the D...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/4188C07D209/10A61P35/00
CPCA61K31/4188A61K45/00C07D209/10A61K2300/00A61K31/135A61K31/138A61K31/352A61K31/353A61K31/381A61K31/404A61K31/5375A61P35/00
Inventor J·C·施佛罗伦斯·M.·霍夫曼托马斯·C.·陈
Owner UNIV OF SOUTHERN CALIFORNIA
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