Application of ODC1 and its inhibitors in the diagnosis and treatment of tamoxifen resistance in breast cancer
The diagnosis and prediction of tamoxifen resistance in breast cancer was carried out by ODC1 as a marker, and the combination of DFMO and tamoxifen treatment was used to solve the problem of tamoxifen resistance in patients with ERα-positive breast cancer in the prior art, which significantly inhibited the proliferation of breast cancer cells.
Patent Information
- Application Number
- CN202311759824.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-20
- Publication Date
- 2025-03-11
- Estimated Expiration
- 2043-12-20
AI Technical Summary
The prior art is difficult to effectively diagnose and treat tamoxifen resistance in patients with ERα-positive breast cancer, resulting in recurrence, metastasis and death.
ODC1 is used as a marker to diagnose and predict tamoxifen resistance in breast cancer, and the ODC1 inhibitor DFMO is used alone or in combination with tamoxifen to inhibit the proliferation of ERα-positive breast cancer cells.
ODC1 overexpression can be used as a marker for judging or predicting tamoxifen resistance in breast cancer. DFMO combined with tamoxifen therapy significantly inhibits the proliferation of ERα-positive breast cancer cells and other moxifen-resistant breast cancer cells, and has great application value.
Smart Images
Figure CN117701715B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biopharmaceuticals, and in particular to application of ODC1 and an inhibitor thereof in diagnosis and treatment of tamoxifen resistance in breast cancer. Background Art
[0002] Breast cancer is one of the most common malignant tumors in women today. More than 70% of breast cancer patients are estrogen receptor (ERα) positive. Tamoxifen is the main endocrine therapy for ERα-positive breast cancer patients. As the duration of use increases, about one-third of patients will develop tamoxifen resistance. Recurrence and metastasis caused by tamoxifen resistance is an important factor in the death of breast cancer patients. Therefore, revealing the key molecules that induce tamoxifen resistance in ERα-positive breast cancer and developing new treatment strategies for tamoxifen-resistant breast cancer are of great significance to maintaining women's life and health.
[0003] A large number of studies have shown that the arginine / ornithine metabolic pathway is abnormally activated in a variety of malignant tumors, and arginine / ornithine small molecule metabolites such as putrescine and polyamine small molecules such as spermine can significantly promote the malignant progression of tumors. Difluoromethylguanine (DFMO), as an irreversible inhibitor of ornithine decarboxylase ODC1, can significantly inhibit the biosynthesis of polyamine small molecules, thereby inhibiting tumor progression. DFMO and combination therapies containing DFMO have been clinically studied in a variety of malignant tumors such as brain glioma, small cell lung cancer, Hodgkin's lymphoma, and gastrointestinal tumors. DFMO has shown positive anti-cancer effects in a variety of malignant tumors. Summary of the invention
[0004] In order to overcome the shortcomings and deficiencies in the prior art, the object of the present invention is to provide an application of ODC1 and its inhibitors in the diagnosis and treatment of tamoxifen resistance in breast cancer.
[0005] The purpose of the present invention is achieved through the following technical solution: use of ODC1 as a marker in the preparation of a reagent for diagnosing tamoxifen resistance in breast cancer.
[0006] Another object of the present invention is achieved by the following technical solution: use of an ODC1 inhibitor in the preparation of a drug for breast cancer.
[0007] Preferably, the ODC1 inhibitor is DFMO.
[0008] Preferably, the breast cancer is ERα-positive breast cancer.
[0009] Another object of the present invention is achieved by the following technical solution: use of an ODC1 inhibitor in the preparation of a drug for improving drug resistance of patients to breast cancer.
[0010] Preferably, the ODC1 inhibitor is DFMO.
[0011] Preferably, the breast cancer drug resistance refers to tamoxifen resistance in breast cancer.
[0012] Another object of the present invention is achieved by the following technical solution: use of an ODC1 inhibitor and tamoxifen in the preparation of a drug for breast cancer.
[0013] Preferably, the ODC1 inhibitor is DFMO.
[0014] Preferably, the breast cancer is ERα-positive breast cancer.
[0015] The beneficial effects of the present invention are as follows: the present invention has found that ODC1 is overexpressed in tamoxifen-resistant breast cancer cells, and thus ODC1 overexpression can be used as a marker for judging or predicting tamoxifen resistance in breast cancer; in addition, the present invention has found that the ODC1 inhibitor DFMO can significantly inhibit the proliferation of ERα-positive breast cancer cells and other tamoxifen-resistant breast cancer cells when used as a single drug or in combination with tamoxifen. Therefore, the present invention uses ornithine metabolism-related gene ODC1 as a diagnostic and predictive marker for tamoxifen resistance in breast cancer, and the combined therapy of DFMO combined with tamoxifen has great application value in the diagnosis and treatment of tamoxifen-resistant breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 The present invention is to detect the mRNA expression of ODC1 in tamoxifen-sensitive cells MCF-7 and tamoxifen-resistant cells MCF-7TAMR.
[0017] Figure 2 The present invention is a clone formation experiment to detect cell proliferation changes, wherein A and B are cell pictures and statistical charts of the effects of DFMO and tamoxifen alone or in combination on MCF-7 cell proliferation; C and D are cell pictures and statistical charts of the effects of DFMO and tamoxifen alone or in combination on MCF-7TAMR cell proliferation.
[0018] Figure 3 The CCK8 proliferation assay of the present invention detects the proliferation changes of tamoxifen-resistant breast cancer cells.
[0019] Figure 4 The AnnexinV / PI apoptosis experiment of the present invention detects apoptosis changes in tamoxifen-resistant breast cancer cells. DETAILED DESCRIPTION
[0020] In order to facilitate the understanding of those skilled in the art, the following embodiments and attached Figure 1-4 The present invention is further described, and the contents mentioned in the implementation modes are not intended to limit the present invention.
[0021] Example 1: ODC1 is significantly elevated in tamoxifen-resistant breast cancer cells.
[0022] The tamoxifen-sensitive ERα-positive breast cancer cell line MCF7 was used to establish the tamoxifen-resistant breast cancer cell research model MCF7TAMR. The expression of ODC1 mRNA was detected by fluorescence quantitative PCR in the presence or absence of tamoxifen. Figure 1 As shown, the results showed that ODC1 expression was significantly increased in tamoxifen-resistant breast cancer cells.
[0023] Example 2: DFMO combined with tamoxifen can significantly inhibit the proliferation of ERα-positive breast cancer cells.
[0024] Tamoxifen-sensitive MCF-7 cells and tamoxifen-resistant MCF-7TAMR cells were treated with tamoxifen or DFMO alone, and the above two drugs were used in combination to treat MCF-7 breast cancer cells and their resistant MCF-7TAMR cells. The clone formation assay was used to detect the effects of the above treatments on the proliferation of the two cells. The experimental results are shown in Figure 2. Figure 2 As shown, the results showed that tamoxifen alone could only partially inhibit the proliferation of MCF-7 cells, and had no inhibitory effect on tamoxifen-resistant cells MCF-7TAMR; DFMO alone could significantly inhibit the proliferation of MCF-7 cells and other tamoxifen-resistant cells, and showed a stronger inhibitory effect on both cells when combined with tamoxifen.
[0025] Example 3: CCK8 cell proliferation assay to detect proliferation changes of tamoxifen-resistant breast cancer cells
[0026] In order to further verify the inhibitory effect of DFMO on tamoxifen-resistant breast cancer, the present invention further used a CCK8 cell proliferation detection kit to detect the effect of DFMO alone or in combination with tamoxifen on the proliferation and apoptosis of tamoxifen-resistant breast cancer cells. The CCK8 proliferation detection results are shown in Figure 2. Figure 3 As shown, the results showed that DFMO treatment alone could significantly inhibit the proliferation of MCF-7 tamoxifen-resistant cells, and combined with tamoxifen treatment showed a stronger proliferation inhibitory effect on tamoxifen-resistant breast cancer cells.
[0027] Example 4: Annexin V / PI flow cytometry apoptosis assay to detect apoptosis changes in tamoxifen-resistant breast cancer cells
[0028] In order to further verify the inhibitory effect of DFMO on tamoxifen-resistant breast cancer, the present invention further used the Annexin V / PI flow apoptosis detection kit to detect the effect of DFMO alone or in combination with tamoxifen on the proliferation and apoptosis of tamoxifen-resistant breast cancer cells. Figure 4 As shown, the results showed that DFMO treatment alone could significantly promote the apoptosis of MCF-7 tamoxifen-resistant cells MCF-7, and combined with tamoxifen treatment showed a stronger apoptosis-inducing effect on tamoxifen-resistant breast cancer cells.
[0029] The above embodiments are preferred implementation schemes of the present invention. In addition, the present invention may also be implemented in other ways. Any obvious replacement without departing from the concept of the present invention is within the protection scope of the present invention.
Claims
1. Use of a reagent for detecting ODC1 in the preparation of a reagent for diagnosing tamoxifen resistance in breast cancer.
2. Use of an ODC1 inhibitor and tamoxifen in the preparation of a drug for improving tamoxifen-resistant breast cancer, characterized in that: The ODC1 inhibitor is DFMO.