CN106581021B - Application of atractyloside and 5-fluorouracil combination in preparation of medicine for preventing and treating rectal cancer - Google Patents
Application of atractyloside and 5-fluorouracil combination in preparation of medicine for preventing and treating rectal cancer Download PDFInfo
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Abstract
The invention discloses application of combination of atractyloside and 5-fluorouracil in preparing a medicine for preventing and treating rectal cancer, wherein the effect of the combined action of the atractyloside and the fluorouracil is obviously better than the inhibition effect of 5 fluorouracil on colorectal cancer cells, and the medicine can effectively inhibit the proliferation of the colorectal cancer cells, so that the medicine is very suitable for preparing the medicine for preventing and treating the rectal cancer, and the medicine for preventing and treating the rectal cancer can effectively inhibit the proliferation of the colorectal cancer cells. The invention is helpful for improving the curative effect of clinical chemotherapeutic drug 5-fluorouracil to control the development and metastasis of colorectal cancer. The method of the invention for inhibiting the proliferation of colorectal cancer cells in vitro can be used to guide the establishment of a method for treating colorectal cancer in vivo.
Description
Technical Field
The invention relates to the field of medicaments for preventing and treating rectal cancer, in particular to application of atractyloside and 5-fluorouracil in preparation of medicaments for preventing and treating rectal cancer.
Background
The incidence of colorectal cancer is third in the world. Although first-line clinical drugs such as 5-fluorouracil, oxaliplatin, FOLFOX, FOLFIRI and other chemotherapeutic drugs or chemotherapeutic regimens are widely used in clinical treatment of colorectal cancer, colorectal cancer patients respond to drugs differently. Although surgical and chemoradiotherapy treatments can alleviate colorectal cancer to some extent, approximately 50% of patients will relapse. Individualized treatment may therefore help to improve the survival health of colorectal cancer patients. However, personalized therapy relies on the application of tumor markers. EGFR, KRAS and hMLHs genes are currently used in the diagnosis, prognosis and treatment of patients with clinical colorectal cancer. However, the development of late-stage drug resistance prevents a certain proportion of patients from continuing to receive the targeted drug therapy, which leads to the deterioration of the disease condition, and therefore, the application of a new molecular target for colorectal cancer is required.
Brother of regulator of imprinted sites (BORIS) is a homologous protein of CCCTC-binding factor (CTCF). The promoter of the BORIS gene is methylated in normal somatic cells and demethylated in testis, ovary, skin and cancer cells. Since BORIS factor binds to the promoter region of tumor testis antigens such as NY-ESO-I, MAGEA, SPANX and TSP50 and demethylates its promoter, BORIS is predicted to be an epigenomic driver of cancer, and may be used in diagnosis, prognosis and treatment.
Earlier studies found that the cancer cells required the BORIS gene. The expression interference of the BORIS gene inhibits the proliferation of the breast cancer cells and induces the apoptosis of the breast cancer cells. It has also been reported that immunization of mice with BORIS DNA immunizes mice against breast cancer. BORIS is aberrantly expressed in colorectal cancer cells, and therefore inhibiting the expression of BORIS gene or inhibiting the expression of BORIS downstream gene in colorectal cancer cells would likely inhibit the proliferation of colorectal cancer cells.
Since BORIS is expressed differentially in colorectal cancer and normal colorectal tissues, where cancer tissues are abnormally expressed and normal tissues are not expressed, it is likely that significant therapeutic effects will be obtained by personalized treatment of colorectal cancer patients with high expression of BORIS using drugs that inhibit the BORIS downstream signaling pathway. The invention has very important significance for treating colorectal cancer.
Disclosure of Invention
The invention provides an application of atractyloside and 5-fluorouracil in preparing a medicine for preventing and treating rectal cancer.
The inventor detects the expression of downstream genes regulated by BORIS by using a gene expression chip method, and finds that the expression of BORIS interferes with the up-regulation of the expression of SEMA3A, XRCC4, PPLL6 and other genes. SEMA3A and XRCC4 genes angiogenesis, branching morphogenesis, axon growth and cell migration. Wherein SEMA3A is a membrane surface protein, and is involved in regulating angiogenesis, branch morphogenesis, axon growth, and cell migration; XRCC4 is a DNA repair enzyme involved in the repair of DNA in the nucleus. Upregulation of SEMA3A and XRCC4 gene expression when BORIS expression was disrupted indicates that a decrease in BORIS expression may lead to the development of apoptosis.
The inventor finds that the similarity between the gene expression profile influenced by the treatment of atractyloside and the gene expression profile influenced by the expression silencing of BORIS is very high by comparing the gene expression profile regulated by the treatment of BORIS with the gene expression profile regulated by the treatment of drugs in a correlation map (CMap) database.
The inventors found that treatment with atractyloside and BORIS expression silencing both resulted in upregulation of SEMA3A, XRCC4 and PPLL6 expression in colorectal cancer cells HCT116 and Caco-2 cells.
The inventor treats colorectal cancer cells HCT116 and Caco-2 by using atractyloside and 5 fluorouracil, and finds that the proliferation of the two cancer cells is inhibited.
Application of atractyloside and 5-fluorouracil in preparation of medicine for preventing and treating rectal cancer is provided.
The copy number and expression value of BORIS gene in colorectal cancer cells are obviously higher than those of normal colorectal cells, and BORIS is a potential diagnosis, prognosis and treatment target of colorectal cancer. We screened drugs in colorectal cancer that function similarly to the interference of BORIS expression. First, we used the gene chip method to detect the change of gene expression profile in the colorectal cancer cell HCT116 and Caco-2 cell when BORIS expression is interfered. Based on the expression profile, we then use the expression profile to screen CMap database for drugs that modulate similar gene expression profiles similar to the interference of BORIS expression. We found that the atractyloside-regulated gene expression profile is similar to the effect of the interference of BORIS expression. The SEMA3A, XRCC4 and PPLL6 genes were expressed in elevated levels both in atractyloside treatment and in interference treatment with BORIS expression. However, atractyloside does not regulate the expression of BORIS gene, indicating that treatment with atractyloside affects the expression of BORIS downstream gene. The atractyloside synergizes 5-fluorouracil to inhibit the proliferation of colorectal cancer cells, and shows that the expression change of the BORIS downstream gene influences the effect of 5-fluorouracil on colorectal cancer. The treatment of the atractyloside is beneficial to improving the inhibition effect of the clinical chemotherapeutic drug 5-fluorouracil on colorectal cancer cells. The method of the invention for inhibiting the proliferation of colorectal cancer cells in vitro can be used to guide the establishment of a method for treating colorectal cancer in vivo.
The molar ratio of the atractyloside to the 5-fluorouracil is 0.5: 0.5-0.7, and preferably, the molar ratio of the atractyloside to the 5-fluorouracil is 0.5: 0.55-0.65, and more preferably, the molar ratio of the atractyloside to the 5-fluorouracil is 0.5: 0.58-0.62, and more preferably, the molar ratio of the atractyloside to the 5-fluorouracil is 0.5: 0.6.
the atractyloside is atractyloside A with CAS number of 126054-77-1.
The rectal cancer is colorectal cancer.
The concentration of atractyloside in the medicine for preventing and treating rectal cancer is 0.3-0.7 mu mol/L, and the concentration of 5 fluorouracil in the medicine for preventing and treating rectal cancer is 0.4-0.8 mu mol/L.
Further preferably, the concentration of atractyloside in the medicine for preventing and treating rectal cancer is 0.4-0.6 mu mol/L, and the concentration of 5 fluorouracil in the medicine for preventing and treating rectal cancer is 0.5-0.7 mu mol/L.
Still more preferably, the concentration of atractyloside in the medicine for preventing and treating rectal cancer is 0.5 mu mol/L, and the concentration of 5 fluorouracil in the medicine for preventing and treating rectal cancer is 0.6 mu mol/L.
The medicine for preventing and treating rectal cancer adopts dimethyl sulfoxide aqueous solution as a solvent, and the volume ratio of the dimethyl sulfoxide aqueous solution is 1: 500000-800000 dimethyl sulfoxide and water, and preferably, the volume ratio of the dimethyl sulfoxide aqueous solution is 1: 666000 dimethyl sulfoxide and water.
Compared with the prior art, the invention has the following advantages:
according to the application of the atractyloside and 5-fluorouracil in the preparation of the medicine for preventing and treating the rectal cancer, the combined effect of the atractyloside and the fluorouracil is obviously better than the inhibition effect of 5 fluorouracil on colorectal cancer cells, and the proliferation of the colorectal cancer cells can be effectively inhibited, so that the medicine is very suitable for preparing the medicine for preventing and treating the rectal cancer, and the medicine for preventing and treating the rectal cancer can effectively inhibit the proliferation of the colorectal cancer cells. The invention is helpful for improving the curative effect of clinical chemotherapeutic drug 5-fluorouracil to control the development and metastasis of colorectal cancer. The method of the invention for inhibiting the proliferation of colorectal cancer cells in vitro can be used to guide the establishment of a method for treating colorectal cancer in vivo. The invention can be popularized and utilized in a market, and has wide application prospect.
Drawings
FIG. 1A is a graph showing that BORIS gene silencing inhibits the proliferation of HCT116 in colorectal cancer cells; FIG. 1, panel B is a graph showing that BORIS gene silencing inhibits proliferation of colorectal cancer cells Caco-2;
FIG. 2 is a gene map of BORIS silencing regulated expression in HCT116 and Caco-2 cells;
FIG. 3A shows screening for drugs similar to expression of BORIS silencing regulator, both HCT116 and Caco-2 cells; FIG. 3B is a graph of the class of drugs in graph A based on the similarity between drugs in the SPIEDw database;
FIG. 4A is a graph of atractyloside-enhanced 5 fluorouracil inhibiting proliferation of colorectal cancer cells (HCT116 cells), and FIG. 4B is a graph of atractyloside-enhanced 5 fluorouracil inhibiting proliferation of colorectal cancer cells (Caco-2 cells);
FIG. 5A is a graph of the regulation of gene expression by BORIS silencing in HCT116 and Caco-2 cells;
FIG. 5B shows the regulation of gene expression in HCT116 and Caco-2 cells by treatment with atractyloside.
Detailed Description
First, cell culture
Colorectal cancer HCT116 and Caco-2 cells in DMEM high-sugar medium containing 10% FBS (fetal bovine serum) by volume percentage at 5% CO by volume percentage2Cultured in an incubator. Cell speciesThe plants were planted in 6-well or 96-well plates for subsequent processing. In gene silencing experiments, RNAiMAX (Thermo Fisher Scientific, Waltham, MA, USA) was used to silence the expression of BORIS. Cell proliferation was detected by the thiazole blue (MTT) method. In this study, the siRNA of BORIS was used to silence the expression of BORIS, and the sequences of the siRNA are shown in Table 1. Atractyloside was purchased from Cayman Chemical Company (Ann Arbor, Michigan, USA). Metronidazole and 5 Fluorouracil are available from Sigma-Aldrich Corporation. Metronidazole (4 μ M), atractyloside (0.5 μ M) and 5 fluorouracil (0.6 μ M) were used for treating colorectal cancer cells alone or in combination, using aqueous dimethyl sulfoxide as solvent, in a volume ratio of 1: 666000 dimethyl sulfoxide and water, wherein the dimethyl sulfoxide water solution is used as negative control during cell processing.
TABLE 1 primer and interfering siRNA
Second, expression chip analysis
3 days after expression of BORIS was silenced by siRNA, RNA was extracted from HCT116 and Caco-2 cells. Gene expression differences were analyzed by AffymetrixPrimeView human gene expression array chips. The silenced samples were compared to control, and genes with two-fold or three-fold altered expression in HCT116 and Caco-2 cells were used to establish a heat map. The original data of the gene expression chip has been stored at NCBI under accession number GSE 86172.
Gene expression profile comparison analysis by using CMap database
SPIEDw (http:// www.spied.org.uk/cgi-bin/wSPIED. cgi) is an online retrieval platform accessible to the CMap database. Inputting the up-and-down-regulated gene expression profile analyzed and found in the gene expression chip into SPIEDw in a proper format to obtain a similar medicine list sorted by the relevance. Positive values represent positive correlations, i.e. drugs with similar regulatory effects on gene expression; negative values represent negative correlations, i.e., drugs that exert opposite regulatory effects on gene expression.
Third, fluorescent quantitative PCR
Treated colorectal cancer cells were extracted with Trizol
(Thermo Fisher Scientific), ethanol precipitation of RNA and reverse transcription into cDNA. The expression level of the candidate gene was detected by fluorescent quantitative PCR. During the detection, GAPDH and actin are used as housekeeping genes. The primers used in the fluorescent quantitative PCR are shown in Table 1.
Fourth, statistical analysis
All assays were performed in triplicate. The significance of the difference is detected by adopting a paired t test, and the difference is represented by P < 0.05.
Five results
1) BORIS gene silencing inhibits colorectal cancer cell proliferation
We silenced the expression of the BORIS gene in colorectal cancer cells and found that silencing BORIS inhibits the proliferation of HCT116 and Caco-2 in colorectal cancer cells (FIG. 1). BORIS is essential for colorectal cancer cells suggesting that silencing the expression of BORIS or its downstream genes in colorectal cancer cells may be useful in the treatment of colorectal cancer. However, the downstream gene regulated by BORIS is unknown.
FIG. 1 shows that BORIS gene silencing inhibits proliferation of colorectal cancer cells HCT116(A) and Caco-2 (B). MTT is used to detect the metabolic activity of cells. Negative sirnas were used as negative controls for BORIS gene silencing. BORIS siRNA is used to silence BORIS gene expression. si-indicates negative siRNA, siBORIS indicates BORIS siRNA.
2) Gene expression chip method for detecting downstream gene regulated by BORIS
We examined the expression of the gene regulated by BORIS by gene expression chip method. In our study, the expression of BORIS gene was first interfered by siRNA method, and then the gene expression regulated by BORIS siRNA was analyzed by Affymetrix PrimeView human genexpression array gene chip. 157 and 703 genes were found to be differentially expressed by more than 2-fold under the control of BORIS siRNA in Caco-2 and HCT116 cells, respectively (FIG. 2). More than 8 genes with 2 times differential expression are regulated and controlled by BORIS siRNA in HCT116 and Caco-2 cells, and the regulation and control directions are the same; of these, 7 were upregulated and 1 was downregulated.
FIG. 2 BORIS silences genes that regulate expression in HCT116 and Caco-2 cells. The figure compares the expression difference value of the BORISsiRNA interfering the 2-fold differentially expressed gene regulated compared with the negative siRNA in HCT116 and Caco-2 cells and the more than 3-fold differentially expressed gene in the two cells. The fold in the figure represents the fold difference in expression of each gene in the BORIS siRNA treated samples compared to the negative siRNA treatment. Genes whose expression differed more than two-fold in both cells are highlighted in parenthesis (up-regulated genes) and asterisks (down-regulated genes).
3) Drug screening based on gene expression profile comparison analysis
Although BORIS silencing greatly inhibits the proliferation of colorectal cancer cells, there is currently no clinical application of siRNA to clinical treatments. Therefore, the small molecular active substance with similar function to the BORIS siRNA can possibly replace the siRNA to be applied to clinic. We compared the expression profile of the gene regulated by the BORIS siRNA with the expression profile of the gene regulated by the small molecule drug in the CMap database. The gene expression profiles regulated by three drugs of Prestwick-1082, metronidazole and atractyloside were found to have the highest similarity to the expression profile regulated by BORISsiRNA (FIG. 3A). Because the relevance and significance ordering of several drugs to BORIS siRNA in HCT116 and Caco-2 is not consistent, we classified the drugs in FIG. 3A based on the data of drug similarity in the CMap database and found that the similarity between metronidazole and atractyloside is higher (FIG. 3B).
FIG. 3 screening for drugs that are similar to expression of the BORIS silencing regulator gene. (A) HCT116 and Caco-2 cells are similar to BORIS silencing drugs. (B) Drugs in graph a are classified according to the similarity between drugs in SPIEDw database. The shades of background colors in the figures indicate the degree of similarity, with lighter colors being more similar. si-indicates negative siRNA, siBORIS indicates BORIS siRNA.
4) Atractylodes glycoside synergistic 5 fluorouracil for inhibiting colorectal cancer cell proliferation
We examined the inhibition of atractyloside and metronidazole on colorectal cancer cells HCT116 and Caco-2 cells, alone and in combination with 5-fluorouracil. The results show that 0.5 mu M atractyloside and 4 mu M metronidazole have no obvious inhibition effect when used for treating the colorectal cancer cells alone, but when 0.5 mu M atractyloside and 0.6 mu M5-fluorouracil are treated in a combined mode, the effect of the combined action of the 0.5 mu M atractyloside and the 0.6 mu M5-fluorouracil is remarkably better than the inhibition effect of the 0.6 mu M5-fluorouracil on the colorectal cancer cells (figure 4). FIG. 4 atractyloside-potentiated 5 fluorouracil inhibited colorectal cancer cell proliferation (A) HCT116 cells, (B) Caco-2 cells. The results were consistent between HCT116 and Caco-2 cells. Atractyloside inhibits the activity of ATP-ADP translocase in cells, and further inhibits oxidative phosphorylation. 5-fluorouracil causes intracellular superoxide production and DNA damage, so atractyloside may promote the inhibitory effect of 5-fluorouracil on colorectal cancer cells by reducing the supply of intracellular energy.
5) Comparing the expression of genes in colorectal cancer cells under the action of BORIS silencing and atractyloside treatment
We examined whether 8 genes found to be differentially expressed 2-fold under the control of BORIS siRNA in the above gene chip were also affected by atractyloside treatment. The results showed that the expression of SEMA3A, XRCC4 and PPIL6 was regulated by atractyloside in the same direction as BORIS siRNA treatment (fig. 5). SEMA3A and XRCC4 are apoptosis-related genes, with SEMA3A involved in angiogenesis, branch morphogenesis, axon growth and cell migration, and XRCC4 involved in DNA damage repair. Treatment of colorectal cancer cells by atractyloside and 5 fluorouracil may be similar to BORIS siRNA regulation of SEMA3A, XRCC4 and PPIL6 expression, and promotes DNA damage and apoptosis of colorectal cancer cells.
FIG. 5 regulation of gene expression by BORIS silencing and atractyloside treatment in HCT116 and Caco-2 cells. (A) BORIS silencing regulates SEMA3A, XRCC4 and PPIL6 gene expression. (B) The atractyloside treatment regulates the expression of SEMA3A, XRCC4 and PPIL6 genes. si-indicates negative siRNA, siBORIS indicates BORIS siRNA.
Claims (7)
1. The application of the combination of atractyloside and 5-fluorouracil in preparing a medicine for preventing and treating rectal cancer is characterized in that the molar ratio of the atractyloside to the 5-fluorouracil is 0.5: 0.5 to 0.7;
the medicine for preventing and treating rectal cancer adopts dimethyl sulfoxide aqueous solution as a solvent, and the volume ratio of the dimethyl sulfoxide aqueous solution is 1: 500000-800000 dimethyl sulfoxide and water;
the concentration of atractyloside in the medicine for preventing and treating rectal cancer is 0.3-0.7 mu mol/L, and the concentration of 5 fluorouracil in the medicine for preventing and treating rectal cancer is 0.4-0.8 mu mol/L.
2. The use according to claim 1, wherein the molar ratio of atractyloside to 5-fluorouracil is 0.5: 0.55 to 0.65.
3. The use according to claim 2, wherein the molar ratio of atractyloside to 5-fluorouracil is 0.5: 0.58 to 0.62.
4. The use according to claim 3, wherein the molar ratio of atractyloside to 5-fluorouracil is 0.5: 0.6.
5. the use according to claim 1, wherein the concentration of atractyloside in the drug for preventing and treating rectal cancer is 0.4-0.6 μmol/L, and the concentration of 5-fluorouracil in the drug for preventing and treating rectal cancer is 0.5-0.7 μmol/L.
6. The use according to claim 5, wherein the concentration of atractyloside in the drug for preventing and treating rectal cancer is 0.5 μmol/L, and the concentration of 5 fluorouracil in the drug for preventing and treating rectal cancer is 0.6 μmol/L.
7. The use according to claim 1, wherein the agent for the prevention and treatment of rectal cancer comprises an aqueous solution of dimethyl sulfoxide as a solvent, wherein the volume ratio of the aqueous solution of dimethyl sulfoxide is 1: 666000 dimethyl sulfoxide and water.
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| CN101437531A (en) * | 2005-11-15 | 2009-05-20 | 康斯塔布制药公司 | Compositions of alpha-fetoprotein and inducers of apoptosis for the treatment of cancer |
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Effective date of registration: 20230703 Address after: Room 604, Floor 6, Building 4, No. 108, Xiangyuan Road, Gongshu District, Hangzhou City, Zhejiang Province, 310000 Patentee after: Zhejiang Xidao Biotechnology Co.,Ltd. Address before: Room 5103, Building 5, Zhejiang Agricultural Science and Technology Innovation Park, No. 198, Shiqiao Road, Shangcheng District, Hangzhou City, Zhejiang Province, 310000 Patentee before: Hangzhou Leyi Health Technology Co.,Ltd. |