CN107970246B - Application of non-steroidal anti-inflammatory drug in improving sensitivity of tumor cells to tyrosine kinase inhibitor - Google Patents
Application of non-steroidal anti-inflammatory drug in improving sensitivity of tumor cells to tyrosine kinase inhibitor Download PDFInfo
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- CN107970246B CN107970246B CN201610919707.1A CN201610919707A CN107970246B CN 107970246 B CN107970246 B CN 107970246B CN 201610919707 A CN201610919707 A CN 201610919707A CN 107970246 B CN107970246 B CN 107970246B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention belongs to the field of new application of known compounds, and particularly discloses application of a non-steroidal anti-inflammatory drug in improving sensitivity of tumor cells to a tyrosine kinase inhibitor, wherein the non-steroidal anti-inflammatory drug is aspirin, ibuprofen or acetaminophen. The invention discovers that non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, acetaminophen and the like can degrade Axl, so that the sensitivity of tumor cells to tyrosine kinase inhibitors is improved. The invention provides good technical support for the wide development of anti-tumor treatment, provides a powerful practical basis for further improving the tumor treatment, and has important development value and popularization significance.
Description
Technical Field
The invention relates to the field of new application of known compounds, in particular to application of non-steroidal anti-inflammatory drugs in improving sensitivity of tumor cells to tyrosine kinase inhibitors.
Background
In the course of cancer treatment, tumor metastasis and drug resistance are two major difficulties affecting the efficacy of anticancer drugs, and are also the main causes of high cancer mortality. Upregulation of Axl expression is closely related to the pathological mechanism of tumor metastasis. Many studies have shown that inhibition of Axl kinase activity can effectively block the growth, migration and invasion of tumor cells. Therefore, the Axl kinase inhibitor is possibly used for patients with early cancer, especially those patients with cancer cell metastasis easily, so that the Axl kinase inhibitor can exert the curative effect to the maximum extent.
The mechanism by which resistance is conferred upon treatment of patients with receptor tyrosine kinase inhibitors is generally secondary mutations of the targeted kinase or compensatory upregulation of other receptor tyrosine kinases. Overexpression of Axl kinase is believed to be a significant cause of drug resistance due to compensatory upregulation. The synergistic effect of the drug effect of a targeted drug when used in combination with an Axl kinase inhibitor is achieved after the drug resistance has developed. In addition, tumor cells can also develop drug resistance through the mesenchymal transition mechanism of epithelial cells. During this process, overexpression of Axl kinase confers resistance to traditional chemotherapeutic drugs, such as antimitotic drugs, on tumor cells by epithelial-mesenchymal transition. In this case, the Axl inhibitor may be used in combination with a first-line drug to slow the resistance of the patient and thereby inhibit the progression of the cancer.
In recent years, Axl kinase has attracted extensive attention of drug developers as a novel cancer treatment target, and small molecule inhibitors of Axl kinase have become a research hotspot. Kinase inhibitors directed against the Axl target are still being developed at an early stage and relatively little research has been conducted relative to many receptor tyrosine kinase inhibitors. An effective and rapid Axl target inhibitor becomes a hot spot for drug development.
Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs with antipyretic and analgesic effects, and also have anti-inflammatory and antirheumatic effects, and are the first choice for some rheumatic diseases, such as early rheumatoid arthritis, senile arthritis, early ankylosing spondylitis and the like. There is no disclosure in the prior art that non-steroidal anti-inflammatory drugs can also be used to increase the sensitivity of tumor cells to tyrosine kinase inhibitors.
Disclosure of Invention
The present invention overcomes the above-mentioned deficiencies of the prior art by providing the use of non-steroidal anti-inflammatory drugs for increasing the sensitivity of tumor cells to tyrosine kinase inhibitors.
In order to achieve the purpose, the invention is realized by the following technical scheme:
application of a non-steroidal anti-inflammatory drug in preparation of a drug for degrading Axl.
The application of the non-steroidal anti-inflammatory drug in preparing the drug for enhancing the sensitivity of tumor cells to tyrosine kinase inhibitors is that the non-steroidal anti-inflammatory drug is aspirin, acetaminophen or ibuprofen. The invention discloses a tumor cell using a tyrosine kinase inhibitor, which can increase the Axl expression level, and discovers that non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, acetaminophen and the like can induce the degradation of receptor Axl and influence the drug resistance, transfer and relapse of tumors mediated by Axl protein, thereby improving the sensitivity of the tumor cell to the tyrosine kinase inhibitor.
The application of the combination of the non-steroidal anti-inflammatory drug and the tyrosine kinase inhibitor in preparing the anti-tumor drug is that the non-steroidal anti-inflammatory drug is aspirin, acetaminophen or ibuprofen.
A medicine for improving the sensitivity of tumor cells to tyrosine kinase inhibitor contains non-steroidal anti-inflammatory drug (aspirin, acetaminophen or ibuprofen).
An antitumor drug contains a non-steroidal anti-inflammatory drug and a tyrosine kinase inhibitor, wherein the non-steroidal anti-inflammatory drug is aspirin, acetaminophen or ibuprofen.
The medicine can reduce the conversion of epithelial cells to mesenchymal cells, and inhibit tumor metastasis.
The medicine can reduce the formation of tumor stem cells and relieve tumor recurrence.
Compared with the prior art, the invention has the following beneficial effects:
the invention adopts the combination of the non-steroidal anti-inflammatory drug and the tyrosine kinase inhibitor to enhance the sensitivity of the tumor to the tyrosine kinase inhibitor. In vivo and in vitro experiments prove that when the tyrosine kinase inhibitor is used for treating tumors, the non-steroidal anti-inflammatory drug is used in a matching way, so that a stronger tumor killing effect can be obtained.
The invention adopts the combination of the non-steroidal anti-inflammatory drug and the tyrosine kinase inhibitor to inhibit the metastasis of tumors. When the tyrosine kinase inhibitor is used for treating tumors, the non-steroidal anti-inflammatory drug is matched to be used, the expression of the marker protein in the conversion process from epithelial cells to interstitial cells can be obviously reduced, and the formation of lung metastasis is obviously inhibited in a mouse in-vivo model.
The invention adopts the combination of the non-steroidal anti-inflammatory drug and the tyrosine kinase inhibitor, inhibits the formation of tumor stem cells after the targeted drug is used, reduces the expression of specific protein of the tumor stem cells, and inhibits the relapse of tumors after the targeted drug is used for treatment.
The non-steroidal anti-inflammatory drug has been tested by clinical practice for a long time, and a long period for developing new drugs is avoided. The invention has the advantages of low cost, high safety and the like, and provides good technical support for the wide development of anti-tumor treatment. Provides a powerful practical basis for further improving the tumor treatment, and has important development value and popularization significance.
Drawings
Figure 1 is a graph showing the effect of non-steroidal anti-inflammatory drugs on Axl degradation in different tumor cells.
FIG. 2 is a graph of the enhancement of tumor cell sensitivity to tyrosine kinase inhibitors by NSAIDs.
Figure 3 is a graph of the effect of the combination of the non-steroidal anti-inflammatory drug aspirin and trametinib in inhibiting tumor metastasis.
FIG. 4 is a graph of the combination of the NSAIDs aspirin and trametinib for inhibiting the formation of tumor stem cells and the recurrence of tumor after targeted drug administration, wherein in the graph a, the curves from top to bottom represent Vehicle, Asp, Tra + Asp, respectively, based on the 12-value of the abscissa; the columns in the right histogram of FIG. c represent, from left to right, respectively, Vehicle, Asp, Tra + Asp.
Detailed Description
The invention is described in further detail below with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
Degradation of Axl by non-steroidal anti-inflammatory drugs aspirin, acetaminophen or ibuprofen in different tumor cell lines and enhancement of sensitivity of tumor cells to tyrosine kinase inhibitors.
(1) And (3) paving the tumor cell line into a 6-well plate, adding aspirin (Asp), acetaminophen (Ace) and ibuprofen (Ibu) into a cell culture medium when the cell fusion rate reaches 30-40%, and detecting the protein expression amount of Axl after culturing for 48 hours, wherein the concentration of the aspirin, the acetaminophen (Ace) and the ibuprofen (Ibu) is 200 mu M.
(2) The tumor cell line is plated in a 96-well plate, when the cell fusion rate reaches 30-40%, aspirin (Asp), acetaminophen (Ace), ibuprofen (Ibu) are added into a cell culture medium at a concentration of 200 mu M, and tyrosine kinase inhibitors trametinib (Tra), dabrafenib (Dab), sorafenib (Sor) and erlotinib (Erl) are added at the same time. After 48 hours of culture, the activity of the tumor cells was examined using the CCK8 technique.
From the results of the above experiments, it is proved that aspirin, acetaminophen and ibuprofen can degrade Axl in lung cancer, liver cancer, colorectal cancer, breast cancer and melanoma cell lines in vitro cell line experiments (see FIG. 1). At the same time, the killing effect on tumor cells was significantly improved after combination with tyrosine kinase inhibitors (see fig. 2).
Example 2
Taking melanoma as an example, non-steroidal anti-inflammatory drug aspirin (Asp) is used in combination with trametinib (Tra) to inhibit tumor metastasis.
(1) 1 × 106Melanoma cell line A375 was injected subcutaneously into the flank of NOD-SCID mice and following neoplasia, mice were dosed with trametinib (1mg/kg body weight), aspirin (20mg/kg body weight) in vivo on alternate days.
(2) The drug was administered to 14-day mice, and tumor cells were taken and digested into single cell suspensions. Detecting a marker protein in the process of conversion of epithelial cells to mesenchymal cells.
(3) Constructing mouse tumor lung metastasis model by using mouse melanoma cell line B16-F10, 5 × 105Cells were injected into C57 mice from the tail vein, and the mice were dosed with trametinib (1mg/kg body weight), aspirin (20mg/kg body weight), every other day. Lungs from mice were photographed on day 14 of dosing and nodules of lung metastases were counted.
The results of the above experiments show that the combination of aspirin and trametinib can significantly inhibit the expression of a marker protein during the transformation of epithelial cells into mesenchymal cells. And significantly reduced lung metastasis in a model of tumor lung metastasis (see figure 3).
Example 3
Taking melanoma as an example, a non-steroidal anti-inflammatory drug, aspirin (Asp), is used in combination with trametinib (Tra) to inhibit tumor stem cell formation and to inhibit recurrence after targeted tumor administration.
(1) 1 × 106Melanoma cell line A375 was injected subcutaneously into the flank of NOD-SCID mice and following neoplasia, mice were dosed with trametinib Trametinb (1mg/kg body weight), Aspirin Aspirin (20mg/kg body weight) in vivo, on alternate days. The dose was administered to 14 day mice, withdrawn, and tumor volume was continued to be measured.
(2) The cells were administered to 14 day mice, tumor tissues were removed, sectioned, and stem cell protein expression was identified using immunohistochemical techniques. And digesting the tumor tissue into a single cell suspension, and detecting the expression of the stem cell protein by using a flow cytometry technology.
From the results of the above experiments, it can be known that the combination of aspirin and trametinib can significantly inhibit the recurrence after tumor targeted drug administration, and inhibit the formation of tumor stem cells (see fig. 4).
Claims (2)
1. Use of aspirin and trametinib in the preparation of a medicament for inhibiting melanoma metastasis.
2. Application of aspirin and trametinib in preparation of medicine for inhibiting recurrence of melanoma after targeted administration is provided.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610919707.1A CN107970246B (en) | 2016-10-21 | 2016-10-21 | Application of non-steroidal anti-inflammatory drug in improving sensitivity of tumor cells to tyrosine kinase inhibitor |
| PCT/CN2016/108725 WO2018072269A1 (en) | 2016-10-21 | 2016-12-06 | Application of nonsteroidal anti-inflammatory drug for increasing sensitivity of tumor cell to tyrosine kinase inhibitor |
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| CN201610919707.1A CN107970246B (en) | 2016-10-21 | 2016-10-21 | Application of non-steroidal anti-inflammatory drug in improving sensitivity of tumor cells to tyrosine kinase inhibitor |
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| CN107970246A CN107970246A (en) | 2018-05-01 |
| CN107970246B true CN107970246B (en) | 2020-08-28 |
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| US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| BRPI0511967B8 (en) * | 2004-06-11 | 2021-05-25 | Japan Tobacco Inc | 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido[2,3-d] pyrimidine derivatives, their use and pharmaceutical composition comprising them |
| JP4091639B2 (en) * | 2006-03-16 | 2008-05-28 | 成紀 金 | Preventive agent and / or treatment agent for skin disorder caused by tyrosine kinase inhibitor |
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Non-Patent Citations (1)
| Title |
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| Synthesis and Evaluation of Novel Erlotinib−NSAID Conjugates as More Comprehensive Anticancer Agents;Yanmei Zhang等;《ACS Med. Chem. Lett.》;20150908;第A-E页 * |
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| CN107970246A (en) | 2018-05-01 |
| WO2018072269A1 (en) | 2018-04-26 |
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