CN114376997B - Novel IRE1a inhibitor shikonin and disulfiram synergistic anti-tumor combination mode - Google Patents
Novel IRE1a inhibitor shikonin and disulfiram synergistic anti-tumor combination mode Download PDFInfo
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- CN114376997B CN114376997B CN202111178418.8A CN202111178418A CN114376997B CN 114376997 B CN114376997 B CN 114376997B CN 202111178418 A CN202111178418 A CN 202111178418A CN 114376997 B CN114376997 B CN 114376997B
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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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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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
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides a combination mode of shikonin, a novel IRE1a nuclease inhibitor, and a synergistic antineoplastic mode of shikonin and alcohol-stopping medicine disulfiram. The discovery of new targets for shikonin suggests that shikonin may be useful in the treatment of diseases associated with the IRE1a pathway and as a single agent or in combination therapy. The discovery of the synergistic anti-tumor effect of shikonin and the disulfiram with broad-spectrum anti-tumor prospect provides a medicine combination mode for subsequent medicine development.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an IRE1a inhibitor, a combination mode of the IRE1a inhibitor and disulfiram and corresponding therapeutic application of the IRE1a inhibitor.
Background
Protein folding stress in the endoplasmic reticulum of a cell may trigger an unfolded protein response. IRE1a is a key protein in the unfolded protein response, has dual activities of kinase and nuclease, and can activate the splicing of XBP1u messenger RNA into XBP1s messenger RNA in a specific manner so as to relieve protein folding stress, thereby protecting cells from stress-induced apoptosis and promoting tumor growth and angiogenesis. IRE1a inhibitors are useful in the treatment of autoimmune diseases, diabetes, tumors, and microbial infections. Several IRE1a inhibitors have been found to fall into three categories depending on their binding sites: (1) a kinase pocket conjugate; (2) nuclease domain conjugates; (3) no inhibitors of the binding site were confirmed. Kinase pocket conjugates are a class of ligands occupying the IRE1a kinase ATP binding site, inhibiting nuclease-mediated splicing of XBP1 messenger RNA under endoplasmic reticulum stress; the nuclease domain conjugates represented by 4 μ8c all have a common hydroxyaryl aldehyde group that selectively reacts with a specific lysine (Lys 907) of the nuclease domain to form a stable imine through schiff base, effectively preventing XBP1 messenger RNA splicing. Other inhibitors, such as toyocamycin, doxorubicin, triexin and quinotriexin, have been shown to inhibit the IRE1a-XBP1 pathway both in vivo and in vitro, but have no defined mode of action. At present, IRE1a inhibitors are not available in the market, the inhibitors are still in the early development stage, no clinical data for analysis exists, and the IRE1a inhibitors need to be continuously concerned.
Shikonin is a main active ingredient of radix Arnebiae, has anticancer, antiinflammatory, and antibacterial effects, and can be used for treating acute and chronic hepatitis, psoriasis, keratitis, eczema, colpitis, cervicitis, burn, and promoting wound healing. However, the action mechanism and the action target point are not very clear. Duan, D.et al report that shikonin's anticancer mechanism may be that it induces ROS production in the cell mitochondria, resulting in apoptosis and death of cancer cells. At present, shikonin has not been reported to inhibit IRE1a-XBP1 pathway.
The disulfiram of the alcohol-stopping medicine has been found to have broad-spectrum anti-tumor effect in recent years, and active metabolites and action targets thereof are clarified in J.Nature in 2017. Active metabolites of disulfiram bind to NPL4 and induce its aggregation, thereby disabling the important p97 pathway, inducing complex cellular phenotypes leading to cell death. Failure of the p97 pathway induces an unfolded protein response including IRE1a-XBP1, thereby alleviating protein folding stress and protecting cells from stress-induced apoptosis. Therefore, by using shikonin to inhibit IRE1a, there is a theoretical basis for the synergistic anti-tumor effect with disulfiram.
Disclosure of Invention
The invention provides a combination mode of shikonin, a novel IRE1a nuclease inhibitor, and a synergistic antineoplastic mode of shikonin and alcohol-stopping medicine disulfiram.
The concentration of shikonin was 2.5. Mu.M, and the concentration of disulfiram was 0.25. Mu.M.
The beneficial effects are that:
the shikonin determined by the invention has better inhibition as a novel IRE1a inhibitor.
Drawings
FIG. 1 shows inhibition of human cervical cancer cell line HeLa (FIG. 1A) or human multiple myeloma cell line 8226 (FIG. 1B) XBP1 splicing by Shikonin (SKN) after activation of IRE1-XBP1 induced by the endoplasmic reticulum stress inducer Tunica (TM) and inhibition of human lung cancer cell line A549 XBP1 splicing by SKN after activation of IRE1-XBP1 induced by Disulfiram (DSF) (FIG. 1C). The result shows that SKN has better inhibition on XBP1 splicing within the range of 10-100.
Fig. 2 shows inhibition (%) and synergy score for Shikonin (SKN) and Disulfiram (DSF) at indicated concentrations for human lung cancer cell line a549 alone or in combination [ wherein, plot a is a matrix of inhibition (%) alone or in combination and B is a three-dimensional display of synergy scores; score >0 represents synergy and score <0 represents antagonism. The results show that SKN and DSF have synergistic effect on A549 cells, and the medicine use concentration is 2.5 mu M SKN+0.25 mu M DSF (10:1) when the synergistic score is highest.
Fig. 3 shows inhibition (%) and synergy scores of Shikonin (SKN) and Disulfiram (DSF) at indicated concentrations for the human cervical cancer cell line HeLa alone or in combination. The results show that SKN and DSF also have synergistic effect in HeLa cells, and the drug use concentration is 2.5 mu M SKN+0.25 mu M DSF (10:1) when the synergistic score is highest.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Inhibition of human cervical cancer cell line HeLa (FIG. 1A) and human multiple myeloma cell 8226 (FIG. 1B) XBP1 splicing by Shikonin (SKN) following activation of the endoplasmic reticulum stress inducer Tunicamycin (TM) induced IRE1A-XBP1 and inhibition of human cervical cancer cell line HeLa XBP1 splicing by SKN following activation of the Disulfiram (DSF) induced IRE1A-XBP1 are shown in FIG. 1 (FIG. 1B). The result shows that SKN has better inhibition on XBP1 splicing within the range of 10-100 mu M.
As shown in fig. 2, the inhibition rate (%) of Shikonin (SKN) and Disulfiram (DSF) on human lung cancer cell line a549 alone or in combination and the synergy score at the indicated concentrations [ wherein, fig. a is a matrix of inhibition rate (%) alone or in combination, and B is a three-dimensional display of the synergy score; score >0 represents synergy and score <0 represents antagonism. The results show that SKN and DSF have synergistic effect on A549 cells, and the medicine use concentration is 2.5 mu M SKN+0.25 mu M DSF (10:1) when the synergistic score is highest.
The inhibition (%) and synergy scores of Shikonin (SKN) and Disulfiram (DSF) at indicated concentrations for the human cervical cancer cell line HeLa alone or in combination are shown in fig. 3. The results show that SKN and DSF also have synergistic effect in HeLa cells, and the drug use concentration is 2.5 mu MSKN+0.25 mu M DSF (10:1) when the synergistic score is highest.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (1)
1. The application of combination of shikonin and disulfiram in preparing medicaments for treating lung cancer and cervical cancer is characterized in that the concentration of shikonin is 2.5 mu M, and the concentration of disulfiram is 0.25 mu M.
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| CN109223737A (en) * | 2017-07-10 | 2019-01-18 | 中国中医科学院医学实验中心 | Asian puccoon chlorins compound promotes the application in TRAIL anti-tumor activity medicine in preparation |
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| CN1931152A (en) * | 2006-09-27 | 2007-03-21 | 浙江大学 | Application of shikonin in preparing medicine for inducing apoptosis |
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| CN109223737A (en) * | 2017-07-10 | 2019-01-18 | 中国中医科学院医学实验中心 | Asian puccoon chlorins compound promotes the application in TRAIL anti-tumor activity medicine in preparation |
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