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Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound

A technology of glucocorticoid and composition, which is applied in the field of composition for treating lung cancer, and can solve the problems that research has not yet been carried out in detail

Active Publication Date: 2018-08-21
AJOU UNIV IND ACADEMIC COOP FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, a combined anticancer strategy that inhibits NRF2 and mTORC1 that are activated together in KEAP1 and LKB1 co-mutated NSCLC is expected to be highly effective, however it has not been studied specifically

Method used

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  • Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound
  • Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound
  • Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Screening of NRF2 inhibitors

[0068] (1) Establishment of ARE-luciferase cell line for measuring NRF2 activity

[0069] To screen for potent NRF2 inhibitors, such as figure 1 a shows that the luciferase / green fluorescent protein (GFP: green fluorescent protein) dual antioxidant response element (ARE) capable of monitoring NRF2 activity was established in A549 (LKB1 normal / KEAP1 mutant) non-small cell lung cancer cells with high NRF2 activity : antioxidant responsive element)-DNA base sequence (CACCGTGACTCAGCAATTx3) system (Luciferase / GFP dual ARE-receptor cell line system).

[0070] In order to prove that the luciferase and GFP signals that exhibit high activity in the A549 cell line are specific to NRF2 activity, three kinds of doxycyclin (doxycyclin) with mutually different sequences were prepared as shown in Table 1 below- Inducible NRF2-shRNA. To establish a Tet-inducible shRNA expression system, the following shRNAs were inserted into the tet-pLKO-pyro vector ...

Embodiment 2

[0102] Confirmation of NRF2 inhibition mechanism by clobetasol propionate

[0103] (1) Confirmation of the inhibitory mechanism of clobetasol propionate

[0104] Glucocorticoids act as ligands of nuclear receptor subfamily 3 (nuclear receptor subfamily 3. group C, member 1 ) well known as glucocorticoid receptors (GCreceptor, GCR). When glucocorticoids bind to GCR, GCR induces transcriptional promotion or transcriptional repression of various genes related to various functions in the body such as inflammation or metabolism. Based on these known facts, in order to confirm whether the NRF2 inhibitory effect of the glucocorticoid, clobetasol propionate (Clobetazole propionate) is related to GCR, after using GCR-shRNA to inhibit the expression of GCR, Western blotting and luciferase Determination.

[0105] After first establishing the transduced A549-tet-on cells with vectors including GCR-shRNA, they were treated with doxycycline and clobetasol propionate, and then to perform ...

Embodiment 3

[0122] Confirmation that the expression of NRF2 target protein and the increase of active oxygen are inhibited by clobetasol propionate

[0123] (1) Determination of NRF2 expression in lung cancer cell lines

[0124] It is known that NRF2 is generally expressed more in KEAP1 mutant cells, and protein kinase (p-AMPK) is less expressed in LKB1 mutant cells. To confirm this, immunoblotting was performed on four types of cells. Specifically, in order to verify that H2228 (KEAP1-mutated, LK1-normal), A549 (KEAP1-mutated, LKB1-mutated), H460 (KEAP1-mutated, LKB1-mutated) as KEAP1 mutant cells and H1299 as normal gene cells (KEAP1-normal, LKB1-normal) Whether KEAP1 and LKB1 are mutated, Western blotting is performed by the same method as that performed in Example 1 to confirm the expression levels of NRF2 and p-AMPK.

[0125] results, such as Image 6 As shown in a, due to the high expression of NRF2 in H2228, A549, and H460 cell lines, KEAP1 mutation was confirmed, and based on ...

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Abstract

The present invention relates to a composition for treating or ameliorating lung cancer comprising a glucocorticoid-based compound, a glucocorticoid-based compound and an mTOR inhibitor, or a glucocorticoid-based compound and an AMPK inhibitor as an active ingredient. The glucocorticoid-based compounds inhibit the growth of cancer cells by suppressing NRF2 in KEAP1 mutant lung cancer or KEAP1 andLKB1 mutant lung cancer, and exhibit a more potent anticancer effect when used in combination with the mTOR inhibitor, and thus the compounds can be effectively used as anticancer agents for mutant lung cancer. In addition, one of the characteristics of tumor microenvironments, a low nutrient environment, induces activation of NRF2 and AMPK in KEAP1 and LKB1 normal lung cancer, and the glucocorticoid-based compounds exhibit a strong anticancer synergistic effect in a low nutritional state when treated in combination with an AMPK inhibitor in KEAP1 and LKB1 normal lung cancer, and thus the compounds can also be used as an anticancer agent for KEAP1 normal lung cancer.

Description

technical field [0001] The present invention relates to a composition for treating lung cancer. Background technique [0002] Lung cancer is the second most common cancer in both men and women, accounting for 15% of all cancers. According to a 2011 report by the American Cancer Society, more than 220,000 patients are diagnosed with lung cancer each year, and about 70% of them die, accounting for 27% of all cancer deaths. [0003] Among these lung cancers, non small cell lung cancer (non small lung cancer), as a malignant epithelial tumor (carcinoma), refers to all epithelial lung cancers of non small cell lung cancer (small lung cancer), and accounts for about 85% to 90%. Symptoms of non-small cell lung cancer include persistent cough, chest pain, weight loss, nail damage, joint pain, and shortness of breath. It is detected and treated early and has a high probability of being detected only after it has metastasized to the whole body, including the bones, liver, small int...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/573A61K31/436A23L33/10
CPCA61K31/573A61P35/00A61K31/404A61K31/436A23L33/10A23V2002/00A23V2200/308
Inventor 全相玟
Owner AJOU UNIV IND ACADEMIC COOP FOUND
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