CN117982651A - Use of Lisofvllime, CBP-IN-1 IN combination with docetaxel IN the treatment of prostate cancer - Google Patents
Use of Lisofvllime, CBP-IN-1 IN combination with docetaxel IN the treatment of prostate cancer Download PDFInfo
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Abstract
The present invention provides the use of Lisofvllime, CBP-IN-1 IN combination with docetaxel IN the treatment of prostate cancer. The present invention has found that the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway is an important signaling pathway that regulates the sensitivity of prostate cancer docetaxel. STAT4 inhibitor Lisofylline is combined with CBP inhibitor CBP-IN-1 to inhibit the expression of c-MYC through inhibiting the key molecule of IL-11/IL-11RA/JAK1/STAT4/CBP signal path, promote the apoptosis of prostate cancer cells and inhibit the proliferation of the prostate cancer cells, thereby inhibiting the deterioration of tumor microenvironment and the formation of treatment resistance, obviously increasing the treatment sensitivity of docetaxel, reversing the resistance of the prostate cancer docetaxel, and effectively inhibiting or killing the prostate cancer cells which have resistance to the docetaxel. Lisofylline, CBP-IN-1 and docetaxel combined can generate obvious synergistic effect, obviously inhibit the progress of prostate cancer and reduce the weight and volume of tumors. Thus, lower doses of docetaxel may be used in combination therapy, thereby reducing the side effects of chemotherapy and improving the quality of life of the patient.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an application of Lisofvllime, CBP-IN-1 and docetaxel IN combination IN treating prostate cancer.
Background
In the field of prostate cancer treatment, docetaxel is a commonly used chemotherapeutic drug whose effect is limited by the response of tumor cells to the drug. The adaptability and variability of tumor cells results in resistance to conventional chemotherapy, a phenomenon common to patients with long-term chemotherapy. This resistance not only limits the efficacy of chemotherapeutic drugs, but may also promote the survival and proliferation of tumor cells, leading to disease progression. Therefore, the sensitivity of the prostate cancer to docetaxel is improved, and the docetaxel resistance is reversed, so that the survival rate of patients is hopeful to be improved, and the life quality of the patients is likely to be improved. Thus, there is a need in the art for new therapeutic strategies that overcome the traditional limitations in prostate cancer treatment and improve efficacy.
Lisofylline and CBP-IN-1 are two novel drugs, lisofylline, which act as inhibitors of STAT4 and have the ability to modulate immune responses and inhibit inflammation. CBP-IN-1, however, acts as a CBP inhibitor and is able to interfere with the signaling pathway of tumor cells.
Disclosure of Invention
Based on this, it is an object of the present invention to provide the use of Lisofvllime, CBP-IN-1 IN combination with docetaxel IN the treatment of prostate cancer. Lisofvllime IN combination with CBP-IN-1 can reverse prostate cancer docetaxel resistance and provide therapeutic sensitivity.
In order to achieve the above purpose, the present invention adopts the following technical scheme.
In a first aspect of the invention there is provided the use of an agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway in the manufacture of a medicament for reversing docetaxel resistance of prostate cancer.
In some embodiments, the agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway is a STAT4 inhibitor and a CBP inhibitor.
In some embodiments, the STAT4 inhibitor is Lisofylline; and/or, the CBP inhibitor is CBP-IN-1.
In some embodiments, the agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway promotes apoptosis of prostate cancer cells by inhibiting expression of c-MYC, inhibiting proliferation of prostate cancer cells.
IN a second aspect of the present invention, there is provided a medicament for reversing the resistance of prostate cancer docetaxel, the active ingredients of the medicament comprising Lisofylline and CBP-IN-1; the Lisofylline and CBP-IN-1 are each separate administration units, or the Lisofylline and CBP-IN-1 together form a combined administration unit.
In a third aspect of the invention there is provided the use of an agent that inhibits or down regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway in combination with docetaxel in the manufacture of a medicament for the treatment of prostate cancer.
In some embodiments, the agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway is a STAT4 inhibitor and a CBP inhibitor.
In some embodiments, the STAT4 inhibitor is Lisofylline; and/or, the CBP inhibitor is CBP-IN-1.
In some embodiments, the prostate cancer is docetaxel resistant prostate cancer.
IN a fourth aspect of the present invention, there is provided a combination for the treatment of prostate cancer, the active ingredients of the medicament comprising Lisofylline, CBP-IN-1 and docetaxel; the Lisofylline, CBP-IN-1 and docetaxel are separate administration units, or the Lisofylline, CBP-IN-1 and docetaxel are combined together to form a combined administration unit.
The present invention has found that the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway is an important signaling pathway that regulates the sensitivity of prostate cancer docetaxel. STAT4 inhibitor Lisofylline is combined with CBP inhibitor CBP-IN-1 to inhibit the expression of c-MYC through inhibiting the key molecule of IL-11/IL-11RA/JAK1/STAT4/CBP signal path, promote the apoptosis of prostate cancer cells and inhibit the proliferation of the prostate cancer cells, thereby inhibiting the deterioration of tumor microenvironment and the formation of treatment resistance, obviously increasing the treatment sensitivity of docetaxel, reversing the resistance of the prostate cancer docetaxel, and effectively inhibiting or killing the prostate cancer cells which have resistance to the docetaxel.
IN addition, lisofylline, CBP-IN-1 and docetaxel combined can generate obvious synergistic effect, obviously inhibit the progress of prostate cancer and reduce the weight and volume of tumors. Thus, lower doses of docetaxel may be used in combination therapy, thereby reducing the side effects of chemotherapy and improving the quality of life of the patient.
The invention provides a new treatment option for prostate cancer patients with poor standard treatment effect, especially prostate cancer patients who have developed resistance to docetaxel, and provides more effective and safer treatment options for prostate cancer patients.
Drawings
FIG. 1 shows the results of signal pathway analysis in a docetaxel drug resistant prostate cancer organoid model.
FIG. 2 is a graph showing the results of a study of the potential role of IL-11 and its receptor IL-11RA in the sensitivity and resistance of prostate cancer docetaxel treatment.
FIG. 3 shows the results of a study of the mechanism of action of STAT4 and CBP downstream of IL-11/IL-11RA in docetaxel resistant cells.
FIG. 4 shows the results of co-immunoprecipitation and reporter gene experiments.
FIG. 5 is a graph showing the results of IN vitro synergy evaluation of Lisofylline, CBP-IN-1 and docetaxel combination.
FIG. 6 shows the results of an IN vivo pharmacodynamic study of Lisofylline, CBP-IN-1 and docetaxel combination.
Detailed Description
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the description of the association relationship of the association object, referred to as "and/or", means that there may be three relationships, for example, a and/or B may mean: a exists alone, A and B exist together, and B exists alone.
The following description is made with reference to specific embodiments. All experimental data were subjected to appropriate statistical analysis in the examples below, and group comparisons were made using t-test and analysis of variance (ANOVA). The experimental results are presented in graphical form.
EXAMPLE 1 analysis of IL-11/IL-11RA signalling pathways in docetaxel resistant prostate cancer organoids model
In our search for a mechanism of prostate cancer docetaxel resistance, we first examined the RNA expression profiles of three prostate cancer organoids models (i.e., MSK-PCa3, MSK-PCa7 and PM 154). These expression profiles were from the GSE162285 dataset. We performed differential expression analysis of docetaxel drug resistant samples versus untreated control samples in these three organoid models using limma package in the R language. We established stringent significance criteria, thresholding the differential expression to a P value of less than 0.05. By this rigorous analysis method we identified a set of 130 genes that were consistently differentially expressed in all three organoid models (fig. 1A).
To better understand our findings, we compared the RNA expression profile of these 130 genes with the expression profile of tumor and adjacent normal tissues in the TCGA-PRAD cohort. 117 of the 130 genes identified from the organoid model were detectable in the TCGA-PRAD dataset, underscores their potential relevance in a broader clinical setting (fig. 1B).
By single factor Cox regression analysis we identified three molecules of IL-11, TRAF1 and DHRS2 in the risk factor gene that were up-regulated in the docetaxel resistant group, indicating consistent progression and poor prognosis of tumor docetaxel resistance (fig. 1C-F).
In addition, in the TCGA-PRAD cohort, IL-11 expression was significantly increased in patients with higher T-stage, and IL-11 expression was also significantly increased in patients with high Gleason scores (FIGS. 2A-B). Our transcriptional and translational level validation in local clinical samples also suggested high expression of IL-11 and its receptor IL-11RA in prostate cancer tissues where docetaxel treatment resistance and biochemical recurrence occurred (fig. 2C-F), suggesting a potential role for IL-11 in prostate cancer docetaxel treatment sensitivity and resistance.
EXAMPLE 2 mechanism of action of STAT4 and CBP downstream of IL-11/IL-11RA in docetaxel resistant cells
In our study of the role of IL-11 in the prostate cancer signaling pathway, we used a versatile assay. By using random forest algorithms, we found a clear correlation between IL-11 signaling and activation of key genes within the JAK/STAT pathway (FIGS. 3A-C).
Next, we performed IL-11 overexpression (OE-IL-11) by viral transfection of shRNA for IL-11 in PC3 cells, and IL-11 knock-out (KD-IL-11) by viral transfection of siRNA for IL-11. Alterations in IL-11 levels result in alterations in JAK family kinase expression, with JAK1, JAK2, JAK3 and TYK3 all exhibiting different expression patterns. The results indicate that IL-11 has significant regulatory effects on JAK1 and STAT4 (FIGS. 3D-E), further corroborating the link between IL-11 signaling pathway and STAT 4-mediated transcriptional regulation in prostate cancer.
Further, we performed experiments with PC3, DU145, LNCAP and 22RV1 cells that were validated for over-expression of IL-11, with nonspecific empty load as a control. After 48 hours of treatment, cells were collected, total protein was detected and extracted, and the expression of the relevant protein was detected using WB. WB experiments further demonstrate at the protein level that overexpression of IL-11 regulates downstream signaling molecules like JAK1 and STAT4, indicating the regulatory role of the autocrine active IL-11/IL-11RA signaling axis in these cells (fig. 3F).
Furthermore, the key role of IL-11 in JAK/STAT pathway activation in prostate cancer was demonstrated by significant changes in the expression and phosphorylation levels of JAK1 and STAT4 following blocking of the IL-11 signaling pathway in PC3 and DU145 cells with either IL-11 neutralizer (10 ng/ml) or IL-11RA antagonist (10 ng/ml) (FIG. 3G).
Further, we analyzed the transcriptional regulation pattern of pSTAT4 in docetaxel resistant and sensitive cells using ChIP-seq technology. The experimental method is as follows: the treated cells were crosslinked with 1% formaldehyde for 10 minutes and then lysed with SDS lysis buffer. Chromatin was disrupted by sonication and the supernatant was immunoprecipitated overnight at4 ℃ using a specific antibody directed against phosphorylated STAT 4. IgG was used as a negative control, the complex formed by protein A/G beads with antibodies and chromatin was washed with low-salt, high-salt and LiCl wash buffers in sequence, and finally the relevant chromatin fragments were released with elution buffer. The cross-linking in the DNA-protein complex is then reversed and DNA purification is performed by spin column chromatography. Enrichment of the target DNA sequence was quantified by quantitative PCR (qPCR) and the products were simultaneously sequenced.
The results are shown in FIGS. 4A-C. The interaction between pSTAT4 and CBP and its role in regulating c-MYC transcriptional activity was further confirmed by co-immunoprecipitation and reporter experiments (fig. 4D-E).
Example 3Lisofylline, CBP-IN-1 and docetaxel combination synergistic Effect evaluation
Based on the results of previous studies, we identified a key role for IL-11/IL-11RA/JAK1/STA4/CBP/c-MYC signaling pathway in regulating the therapeutic effects of docetaxel in prostate cancer. We have further explored whether multi-target combinatorial therapies directed against key molecules in the signaling pathway could help to improve therapeutic efficacy and overcome the clinical challenges of docetaxel treatment resistance.
The prostate cancer cell line was exposed to Lisofylline, CBP-IN-1 and docetaxel, alone or IN combination, under IN vitro conditions. The specific method comprises the following steps: prostate cancer cells (PC 3) were treated with Lisofylline, CBP-IN-1 and DTX, respectively, at different concentrations for 48 hours. Cell viability was measured by MTT assay. Calculation of the half maximal inhibitory concentration (IC 50) and plotting of the dose-response curve were both done using GRAPHPAD PRISM software. To test the synergistic effect of Lisofylline, CBP-IN-1 and docetaxel, PC3 and DU145 cells were treated with either drug alone or IN combination, respectively, and then the viability of the cells was measured by MTT assay.
The dose response curve and IC50 values of the single drug treated prostate cancer cell line were first calculated and the synergy index (CI) of the combination was calculated using Calcusyn software, CI less than 1.0 being considered a synergy.
The results suggest that Lisofylline alone did not have significant cancer suppression (specific data omitted). The IC50 value of the PC3 cell Docetaxel (DTX) alone treatment group was 3.706nM (FIG. 5A), and the IC50 value of the CBP-IN-1 alone treatment group was 1.677nM (FIG. 5B); triple administration had a significant synergistic effect with a CI value of 0.6123 (fig. 5C). The DU145 cell docetaxel alone treatment group had an IC50 value of 4.418nM (FIG. 5D), the CBP-IN-1 alone treatment group had an IC50 value of 2.141nM (FIG. 5E), and the triple drug had a significant synergistic effect with a CI value of 0.6620 (FIG. 5F).
EXAMPLE 4 in vivo pharmacodynamics Studies
This example further evaluates the antitumor effects of Lisofylline, CBP-IN-1 and docetaxel, alone or IN combination, IN a mouse prostate cancer xenograft model.
The experimental method comprises the following steps: constructing a mouse prostate cancer xenograft model: the experiments used 4-week old male BALB/c nude mice as subjects. These mice were injected with 1×10 6 numbers of PC3 cells. When tumors were palpable, mice were randomly divided into 5 groups (6 per group) and received different treatments with the following groupings, respectively: (1) Lisofylline treatment group: lisofylline,25mg/kg, intraperitoneal injection, 1 time a day; (2) CBP-IN-1 treatment group: CBP-IN-1, 25mg/kg, lavage, 1 time daily; (3) DTX processing group: DTX,7mg/kg, intravenous injection, 1 time daily; (4) Combined treatment group Combine: DTX,7mg/kg, intravenous injection, 1 time daily; lisofylline,25mg/kg, intraperitoneal injection, 1 time a day; CBP-IN-1, 25mg/kg, lavage, 1 time daily; (5) control group Ctrl: the same volume of PBS was used for intravenous injection as group 3, 1 time daily. After the drug administration treatment, tumor size was measured every other day using calipers, and tumor volume was calculated using the formula v=0.5×length×width 2. After completion of the study, mice were humanly sacrificed and tumor tissues were collected for further analysis.
The IN vivo (IN situ oncology) results also agree with the IN vitro results, and Lisofylline, CBP-IN-1 and docetaxel three drug combination treatment group significantly inhibited prostate cancer progression IN vivo compared to Lisofylline, CBP-IN-1 and docetaxel alone treatment group (fig. 6).
IN summary, the invention fully evaluates the effect of the combination of Lisofylline, CBP-IN-1 and docetaxel on docetaxel-resistant prostate cancer cells, particularly against modulation of the IL-11/IL-11RA signaling pathway, and the synergistic effect of these agents IN inhibiting tumor growth and promoting docetaxel sensitivity.
The technical features of the above embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. Use of an agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway in the manufacture of a medicament for reversing docetaxel resistance of prostate cancer.
2. The use according to claim 1, wherein the inhibition or downregulation
Agents of the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway are STAT4 inhibitors and CBP inhibitors.
3. The use of claim 2, wherein the STAT4 inhibitor is Lisofylline; and/or, the CBP inhibitor is CBP-IN-1.
4. The use according to claim 1, wherein the inhibition or downregulation
Agents of the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway promote apoptosis of prostate cancer cells and inhibit proliferation of prostate cancer cells by inhibiting expression of c-MYC.
5. A medicament for reversing prostate cancer docetaxel resistance, wherein the active ingredients of the medicament comprise Lisofylline and CBP-IN-1; the Lisofylline and CBP-IN-1 are each separate administration units, or the Lisofylline and CBP-IN-1 together form a combined administration unit.
6. Use of an agent that inhibits or down-regulates the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway in combination with docetaxel for the preparation of a medicament for treating prostate cancer.
7. The use according to claim 6, wherein the inhibition or downregulation
Agents of the IL-11/IL-11RA/JAK1/STAT4/CBP signaling pathway are STAT4 inhibitors and CBP inhibitors.
8. The use of claim 7, wherein the STAT4 inhibitor is Lisofylline; and/or, the CBP inhibitor is CBP-IN-1.
9. The use according to any one of claims 6 to 8, wherein the prostate cancer is docetaxel resistant prostate cancer.
10. A combination for the treatment of prostate cancer, wherein the active ingredients of the combination comprise Lisofylline, CBP-IN-1 and docetaxel; the Lisofylline, CBP-IN-1 and docetaxel are separate administration units, or the Lisofylline, CBP-IN-1 and docetaxel are combined together to form a combined administration unit.
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