This application is a national phase entry under 35 U.S.C. § 371 of International Application No. PCT/CN2015/000478, filed Jun. 30, 2015, the content of which is hereby incorporated by reference in its entirety.
The present invention relates to the technical field of biology, and it particularly relates to the application of nicardipine in the preparation of anti-lung cancer products.
Cancer is the most common as well as the most serious disease that threatens human health, and developing effective anti-cancer medications is critical to extending patients' lives. Along with the rapid development of cancer genomics and molecular pharmacology in recent years, the development of new anti-cancer medications has had relatively good outcomes. However, since the bottlenecks of large investments required in the development of new medications and the long-time periods cannot be overcome, as well as the great individual variation in tumor genetics, many traditional anti-cancer medications are not very effective, new medications are expensive, and side effects are not well understood.
In a paper published by the researchers Barabasi A L et. al. in the 2011 Nature Reviews Genetics, a molecular network analysis conducted based on GWAS findings and an interactome strategy is expected to reveal new drug targets and molecular markers for complex diseases, and ultimately to provide an entirely new understanding of disease pathogenesis and treatment approaches. Even more noteworthy is that it has been discovered in drug repositioning studies that susceptibility genes locked in by GWAS studies as well as their genes with protein-protein interaction (PPI) can more easily become indirect targets for medications. This discovery aids in explaining the mechanisms of action of currently available drugs as well as guiding new drug research. In 2014, researchers Okada Y et. al. published a paper in Nature showing that out of the 101 susceptibility genes for rheumatoid arthritis found through a meta-analysis of GWAS findings, 98 are currently being used as direct or indirect targets for rheumatoid arthritis medications. They also discovered through drug repositioning research that there are dozens of medications that have been approved for use for other indications that could be used to treat rheumatoid arthritis.
This research was carried out through integrating cancer gene profiles of the Cancer Gene Census of the Cosmic version 72 cancer histological database as well as the protein interactions in the STRING version 10 database with Drug Bank Version 4.2, the database of FDA approved medications. This obtained candidates for drug repositioning and screening tests for tumor cell lines were carried out, revealing new anti-cancer drugs. Candidates for tumor suppressing drugs revealed from the cancer cell line screening are as follows:
nicardipine, promethazine, estrone, nicardipine, sulindac, etonogestrel, levonorgestrel, mesalazine, indomethacin, sulfasalazine, blsalazide, irbesartan, ibuprofen, isoprenaline, and pentosan polysulfate.
The primary goal of this invention is to provide a new use for nicardipine.
This invention provides uses for nicardipine in the preparation of products to treat lung cancer.
The second goal of this invention is to provide a new use for nicardipine.
This invention provides uses for nicardipine the preparation of products to inhibit the proliferation of lung cancer cells.
The third goal of this invention is to provide a new use for nicardipine.
This invention provides uses for nicardipine in the preparation of products to reduce IC50 values in lung cancer cells.
Uses of nicardipine in treating lung cancer are also within scope of protection of this invention;
In the uses above, the lung cancer cells mentioned are small-cell lung cancer or non-small cell lung cancer cells; the non-small cell lung cancer cells are specifically NCI-H524; the small-cell lung cancer cells are specifically NCI-H446.
In the uses above, the product is a medication or reagent kit.
The fourth goal of this invention is to provide a kind of product.
The active ingredient in the product of this invention is nicardipine, and it has at least one of the following functions:
In the products mentioned above, the lung cancer cells mentioned are small-cell lung cancer or non-small cell lung cancer cells; the non-small cell lung cancer cells are specifically NCI-H524; the small-cell lung cancer cells are specifically NCI-H446.
In the product above, the product is a medication or reagent kit.
Unless otherwise specified, the experimental methods employed in the following examples are standard methods.
Materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified, and the experimental methods employed in the following examples are standard methods.
The analyte drug in the following examples is nicardipine, and its chemical composition is as follows:
It is a drug bank product with a catalog number of DB00622 (APRD00088).
In the examples below, the product sources for the NCI-H524 non-small cell lung cancer cells, the NCI-H446 small-cell lung cancer cells, the SNU-449 human hepatoma cells, and the NCI-H810 human lung cancer cells, are as follows:
The primary instruments and materials in the examples below are:
In example 1, CELLTITER-GLO was used to test nicardipine against non-small cell lung cancer.
A. Test Plate Preparation
1. Cell plating
The complete medium for NCI-H524 cells was RPMI-1640 (a live product), Cat #A1049101, with a cells/well density of 16000.
The complete medium for NCI-H446 cells was RPMI-1640 (a live product), Cat #A1049101, with a cells/well density of 8000.
2. The drug analyte nicardipine was prepared and administered (200× final concentration):
1) The master plate for the drug analyte nicardipine was prepared
2) Doxorubicin positive medication (MCE, Cat. No. HY-15142) master plate preparation
3. Drug working board preparation and dosing
Wells with no medication added acted as controls.
The final concentrations and dosing of the analyte drug, positive medication Doxorubicin, and control in the 96-well plates were as follows:
The final concentrations (μM) of the analyte drug in wells 2-10 in
The final concentration (μM) of the positive medication Doxorubicin in wells 2-10 in
In addition, the S1208 well in the 96-well plate (E1-H1 and A12-D12): 10 μl of the final concentration 100 μM Doxorubicin solution (solvent containing 0.5% DMSO complete culture medium solution), DMSO wells (A1-D1, E12-H12, and A11-H11): 10 μl containing 0.5% DMSO complete culture medium solution.
B. CELLTITER-GLO Luminescent Cell Viability Assay System
1. CellTiter-Glo reagent preparation
2. Testing
The results of the NCI-H524 96-well drug screening plate are shown in
The results of the NCI-H446 96-well drug screening plate are shown in
The IC50 value was calculated; results are shown in Table 1.
The same method was used to test nicardipine's action on the IC50 values of SNU-449 human hepatoma cells and NCI-H810 human hepatoma cells; results are shown in Table 1.
It is evident that nicardipine has a specific inhibitory effect on the proliferation of non-small cell cancer cells and it can be used as a medication for non-small cell lung cancer treatment.
From carrying out cancer drug repositioning for the FDA- and CFDA-approved drug nicardipine, experiments for this invention show, based on screening of non-anti-cancer drugs for various cancer cell lines (tissue types) and mutation sites, that nicardipine has a new use as an anti-small cell lung cancer and/or anti-non small cell lung cancer medication, thus achieving a new purpose for an old drug.
Filing Document | Filing Date | Country | Kind |
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PCT/CN2015/000478 | 6/30/2015 | WO |
Publishing Document | Publishing Date | Country | Kind |
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WO2017/000083 | 1/5/2017 | WO | A |
Number | Name | Date | Kind |
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20060147520 | Ruegg | Jul 2006 | A1 |
20090208493 | Larson | Aug 2009 | A1 |
20110092505 | Burgis | Apr 2011 | A1 |
Number | Date | Country |
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101406473 | Apr 2009 | CN |
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International Search Report and Written Opinion for Appl. Ser. No. PCT/CN2015/000478 dated Apr. 8, 2016 (8 pages). |
Number | Date | Country | |
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20180185346 A1 | Jul 2018 | US |