CN115944648B - New application of butyric acid as sodium selenite anti-colon cancer sensitizer - Google Patents
New application of butyric acid as sodium selenite anti-colon cancer sensitizer Download PDFInfo
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- CN115944648B CN115944648B CN202310231841.2A CN202310231841A CN115944648B CN 115944648 B CN115944648 B CN 115944648B CN 202310231841 A CN202310231841 A CN 202310231841A CN 115944648 B CN115944648 B CN 115944648B
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Abstract
The invention provides a new application of butyric acid as sodium selenite anti-colon cancer sensitizer. The combined treatment of sodium selenite and butyric acid with low concentration can induce colon cancer cells to undergo apoptosis and has a synergistic effect; butyric acid can inhibit sodium selenite-induced upregulation of key proteins of glutamine metabolism ASCT2 and SLC7a11, thereby overcoming the resistance of sodium selenite in colon cancer treatment; the invention provides scientific basis for developing the anti-colon cancer medicament based on sodium selenite and butyric acid, and has great application value.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel application of butyric acid as a sodium selenite anti-colon cancer sensitizer.
Background
Butyric acid is a short chain fatty acid produced by metabolism of dietary fiber by intestinal microorganisms, and the concentration can reach millimole grade. The document reports that butyric acid can prevent colon cancer, inhibit liver metastasis of colon cancer, inhibit proliferation of colon cancer cells and promote apoptosis in vitro. Tributyrin is a precursor of butyric acid, contains a three-molecule butyric acid esterified with glycerol, can be released in the small intestine, can be orally administered, and is well tolerated, so tributyrin is often selected for in vivo experiments.
Selenium is a trace nutrient necessary for human body, sodium selenite is a typical inorganic selenium compound, has better anticancer effect, and can promote oxidation, induce autophagy, inhibit glycolysis, and promote apoptosis and non-apoptotic cell death. In addition, sodium selenite has selective cytotoxicity, and the same dosage of sodium selenite can increase selenium content in tumor by 250 times, while increasing selenium content in normal tissue by 7 times. But is often used as an auxiliary therapeutic drug for tumors in clinic due to the small safety range. The research on the resistance mechanism of sodium selenite is less, and the tumor treatment resistance of sodium selenite is explored and overcome, so that the sodium selenite can play an anticancer role under the condition of low concentration, and the application of sodium selenite in cancer treatment is promoted.
Glutamine is an important nutrient for maintaining tumor growth, and most cancer cells rely on ASCT2 (System alanine-serine-cysteine amino acid transporter-2) for glutamine uptake. SLC7A11 (Solute Carrier Family 7 membrane 11) helps cells take in cystine and remove glutamate, and promotes glutathione synthesis to maintain cell redox status. Both are often highly expressed in tumor cells and are associated with resistance to tumor cell death.
Disclosure of Invention
In a first aspect, the invention provides a pharmaceutical composition comprising sodium selenite and butyric acid. In a specific embodiment, the molar ratio of sodium selenite to butyric acid in the pharmaceutical composition is (0.5-1.5): 400-600, preferably (0.7-1.3): 400-600, (0.8-1.2): 500, (0.9-1.1): 500 or 1:500.
In a second aspect, the invention provides the use of a pharmaceutical composition comprising sodium selenite and butyric acid in the manufacture of a medicament for the treatment of colon cancer; in a specific embodiment, the molar ratio of sodium selenite to butyric acid in the pharmaceutical composition is (0.5-1.5): 400-600, preferably (0.7-1.3): 400-600, (0.8-1.2): 500, (0.9-1.1): 500 or 1:500; in another specific embodiment, the cancer is colon cancer.
The third aspect of the invention is to provide a new use of butyric acid as sodium selenite anticancer sensitizer; in a specific embodiment, the cancer is in particular colon cancer in the application.
The fourth aspect of the invention provides the use of butyric acid in the manufacture of a medicament for enhancing anticancer efficacy of sodium selenite; further, the medicine for enhancing the anticancer effect of sodium selenite is specifically a medicine capable of increasing colon cancer cell apoptosis.
The structural formulas of sodium selenite (CAS: 10102-18-8) and butyric acid (CAS: 107-92-6) used in the invention are shown in formulas (I) and (II);
drawings
FIG. 1 effects of sodium selenite, tributyrin, sodium selenite, and tributyrin combination treatment on mouse body weight, tumor size, and final tumor weight. Sodium selenite, tributyrin, and combinations thereof had no significant effect on mouse body weight. The sodium selenite and the tributyrin are treated independently, so that no obvious inhibition effect on the tumor growth is achieved, and the combined treatment can obviously reduce the tumor size.
Figure 2 effect of sodium selenite and butyric acid treatment on survival of colon cancer cells HCT 116.
Figure 3 effect of sodium selenite and isobutyric acid treatment on survival of colon cancer cells HCT 116.
Figure 4 effect of sodium selenite and succinic acid treatment on survival of colon cancer cells HCT 116.
Figure 5 effect of sodium selenite and acetic acid treatment on survival of colon cancer cells HCT 116.
Figure 6 effect of sodium selenite and propionic acid treatment on survival of colon cancer cells HCT 116.
FIG. 7 effects of sodium selenite and butyric acid treatment on apoptosis-critical proteins c-PARP, bim, glutamine-critical proteins ASCT2 and SLC7A11 of colon cancer cell HCT 116.
Detailed Description
The following detailed description of the embodiments and the technical solutions of the present invention will be made with reference to the accompanying drawings and specific examples, and should be clearly defined: those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention.
The present invention will be described with reference to the following specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, biological materials, etc. used in the examples described below are commercially available unless otherwise specified.
Human colon cancer cells HCT116 were derived from the american type culture collection (American type culture collection), ATCC cell bank.
Example 1 tributyrin enhances the inhibitory effect of sodium selenite on colorectal cancer tumor growth in HCT116 xenograft nude mice model.
The test method comprises the following steps: male BALB/C nude mice (Beijing Veitz laboratory technique Co., ltd.) 24, 6 weeks old, 5X 10 6 HCT116 cells were injected subcutaneously on the right side of the mice and tumor volumes were measured with vernier calipers. When the tumor volume is about 100-120mm 3 At this time, mice were randomly divided into control group, sodium selenite, tributyrin, and combination treatment group. The control group was given an equal amount of physiological saline; the sodium selenite-treated group was administered by intraperitoneal injection every other day at a dose of 2mg/kg (body weight); tributyrin is administered parenterally at a dose of 1g/kg (body weight) 3 times per day. Mice were weighed daily and tumor volumes were measured every other day. After the experiment is finished, the tumor is taken out, and stored at-80 ℃ after liquid nitrogen flash freezing.
With the volume and weight of the tumor as the evaluation criteria, it is clear from fig. 1 that the sodium selenite and the tributyrin alone had no significant inhibitory effect on the tumor growth, and the combination treatment group had significantly inhibited the tumor growth and had no significant effect on the body weight of mice.
The result shows that in the HCT116 tumor cell subcutaneous tumor forming model, the combined treatment of sodium selenite and tributyrin has good therapeutic effect on colon cancer.
Example 2 butyric acid enhances the inhibitory effect of sodium selenite on colon cancer cell growth.
The test method comprises the following steps: HCT116 cells were treated with 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4 and 2.6 μm sodium selenite and 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2 and 1.3mM butyric/isobutyric acid/succinic acid/acetic acid/propionic acid for 30 hours in vitro, cell viability was examined by crystal violet staining and the combination index was calculated from the data. The results shown in fig. 2 demonstrate that the sodium selenite and butyrate combination treatment group significantly reduced HCT116 cell viability, with 0.6 to 1.3mM butyrate in combination with 1.2 to 2.6 μm sodium selenite, and that cell viability was significantly different from that of sodium selenite alone. The combination index of groups 11 were less than 1, indicating that sodium selenite and butyric acid had a synergistic effect in reducing the survival of HCT116 cells at the concentrations selected. And isobutyric acid (fig. 3), succinic acid (fig. 4), acetic acid (fig. 5), and propionic acid (fig. 6) did not further promote reduced cell viability of sodium selenite. The result shows that the butyric acid can enhance the growth inhibition effect of sodium selenite on colon cancer cells, and the butyric acid and the succinic acid have synergistic effect, while the isobutyric acid, the succinic acid, the acetic acid and the propionic acid have no synergistic effect with the sodium selenite respectively.
Example 3 butyric acid reduced sodium selenite-induced upregulation of ASCT2 and SLC7a11 proteins to overcome sodium selenite resistance in colon cancer treatment.
The test method comprises the following steps: HCT116 cells were treated with 2 μm sodium selenite and 1mM butyric acid for 30 hours, and total protein was extracted from the cells and subjected to western blotting. In western blotting detection, the primary antibody for detecting c-PARP was anti-clear-PARP (CST, 9546), the primary antibody for detecting Bim was anti-Bim (CST, 2933), the primary antibody for detecting ASCT2 was anti-ASCT 2 (CST, 8057), the primary antibody for detecting SLC7a11 was anti-SLC 7a11 (CST, 12691), the primary antibody for detecting β -actin was anti- β -actin (CST, 4970), and the secondary antibody was rabbit secondary antibody (MBL, 458). Finally, development was performed using ECL luminescence kit.
The results in FIG. 7 show that treatment of HCT116 cells with 2. Mu.M sodium selenite and 1mM butyric acid alone for 30 hours did not induce cleavage of the apoptosis marker protein PARP and only induced a slight upregulation of the Bim protein, whereas the combination treatment group significantly enhanced cleavage of PARP and upregulation of the Bim protein, indicating that butyric acid enhanced sodium selenite-induced apoptosis of colon cancer cells. The HCT116 cells are independently treated by 2 mu M sodium selenite for 30 hours, so that the protein expression of the glutamine transporter ASCT2 and the cystine/glutamic acid antiport protein SLC7A11 can be enhanced, and the butyric acid can reduce the up-regulation of ASCT2 and SLC7A11 proteins induced by sodium selenite, thereby overcoming the resistance of sodium selenite in colon cancer treatment.
Claims (1)
1. Use of butyric acid in the preparation of a medicament for sodium selenite anti-colon cancer sensitizer, wherein the molar ratio of sodium selenite to butyric acid is (0.9-1.1): 500.
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