Use of inhibitors of histone deacetylases in combination with NASAID for the therapy of cancer and/or inflammatory diseases

A deacetylase and histone technology, applied in allergic diseases, metabolic diseases, drug combinations, etc., can solve the problem of reduced survival of patients with non-small cell lung cancer

Inactive Publication Date: 2008-07-16
TOPOTARGET GERMANY AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patients with non-small cell lung cancer expressing high levels of COX-2 had significantly reduced survival

Method used

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  • Use of inhibitors of histone deacetylases in combination with NASAID for the therapy of cancer and/or inflammatory diseases
  • Use of inhibitors of histone deacetylases in combination with NASAID for the therapy of cancer and/or inflammatory diseases
  • Use of inhibitors of histone deacetylases in combination with NASAID for the therapy of cancer and/or inflammatory diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Downregulation of COX-2 RNA and protein expression by histone deacetylase inhibitors.

[0102] HDAC inhibitors downregulate the expression of Cox-2 (Figure 1 and Figure 2). This can be done for the HDAC inhibitory compound valproic acid (VPA, TSA, G2M-701, G2M-702 and G2M-707 (see WO 2004 / 009536 A1 for a detailed description of G2M-701, G2M-702 and G2M-707) in several Displayed at RNA and protein levels in systems such as A-549 human lung epithelial carcinoma cells, SK-Mel melanoma cells, HT-29 colon carcinoma cells, MDA-MB-231 breast cancer cells, THP- 1 monocytes as well as primary human lymphocytes and macrophages. As shown in Figure 1, the levels of Cox-1 analyzed at the same time were not affected. Conversely, the COX-2 inhibitor celecoxib (Figure 2 ) did not change the expression of COX-2.

[0103] THP-1 cells were induced to differentiate by adding 20 ng / ml of TPA to the growth medium for 3 days. Take 5×10 5 Adherent cells were seeded at a density of 2 cells / ...

Embodiment 2

[0108] Inhibition of prostaglandin secretion by histone deacetylase inhibitors and their combination with COX enzyme inhibitors (NSAIDs).

[0109] Inhibition of Cox-2 protein levels by HDAC inhibitors also resulted in downregulation of prostaglandin secretion in several systems. As shown in Figure 3, this reduction in prostaglandins was achieved to the same level as with the Cox-2 inhibitor celecoxib (Cel).

[0110] In HT-29 colon cancer cells, Cox-2 expression was induced by treatment with 100 ng / ml TNF-α for 4 hours, and in MDA-MB-231 breast cancer cells, 10 μg / ml LPS was used as an inducer of Cox-2 expression Process for 16 hours. HDAC inhibitor and Cox inhibitor treatment were performed 30 minutes before induction (HT-29, MDA-MB-231) or 16 hours before lysis (A549). Prostaglandin levels in supernatants were analyzed using the prostaglandin E2 EIA kit from Cayman according to the manufacturer's instructions. The bars show the mean of the two values, and the error bars re...

Embodiment 3

[0114] Synergistic suppression of adenoma growth in vivo by using a histone deacetylase inhibitor in combination with a Cox-2 inhibitor.

[0115] Treatment with VPA significantly reduced the APC min Adenoma numbers in mouse models. In this model, similar results were obtained by using the Cox-2 inhibitor celecoxib. However, a synergistic reduction in the number of adenomas was observed when both drugs were used in combination in this model. These again strongly demonstrate that the dual activity of VPA, ie its ability to downregulate Cox-2 protein levels and its HDAC inhibitory function, leads to the synergistic efficacy observed when used with conventional Cox-2 inhibitors (Fig. 5A).

[0116] Shown are means with standard error limits of 15 (control group), 17 (VPA group), 13 (celecoxib group) or 5 (combination treatment group) animals per group. P<0.05 (2-sample t-test; control vs VPA and celecoxib treated and monotherapy vs combination treatment treated animals).

[011...

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Abstract

The present invention relates to the medical use of compounds as inhibitors with histone deacetylase activity which when combined with compounds known as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) lead to enhanced beneficial effects in the conditions described below. These symptoms include cancer, cancer-predisposing symptoms, inflammatory and metabolic diseases. Furthermore, the present invention includes the manufacture of a medicament for clinical use in the treatment of the diseases mentioned herein, the administration of the compound as two separate medicaments or the administration of the two medicaments in a single application unit.

Description

technical field [0001] The present invention relates to the medical use of compounds as inhibitors of enzymes with histone deacetylase activity which when combined with compounds known as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) lead to enhanced beneficial effects in the following conditions . These conditions include cancer, cancer predisposing conditions, inflammatory and metabolic diseases. Furthermore, the present invention includes the manufacture of a medicament for clinical use in the treatment of the diseases mentioned herein, the administration of the compound as two separate medicaments or the administration of the two medicaments in a single application unit. Background technique [0002] Chromatin regulation and disease [0003] Local remodeling of chromatin is a critical step in gene transcriptional activation. Nucleosomal packaging of DNA must undergo dynamic changes to bring transcriptional proteins into contact with the DNA template. One of the most...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61P35/00A61K31/19
CPCA61K31/19A61K45/06A61P1/04A61P1/12A61P1/16A61P3/10A61P5/14A61P7/06A61P9/00A61P9/04A61P9/08A61P9/10A61P11/06A61P17/00A61P17/06A61P19/00A61P19/02A61P19/06A61P21/04A61P25/00A61P25/08A61P25/18A61P25/24A61P25/28A61P27/02A61P27/16A61P29/00A61P33/02A61P35/00A61P35/02A61P37/02A61P37/08A61P43/00A61K2300/00
Inventor 西格伦·明克埃尔克·马丁贝恩德·亨奇
Owner TOPOTARGET GERMANY AG
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