Use of a bcl-xl, bcl-2 and bcl-w inhibitor in the manufacture of a medicament for treating sebaceous gland carcinoma of the eyelid

Abstract

The application discloses application of a Bcl-xL, Bcl-2 and Bcl-w inhibitor in preparation of a medicine for treating eyelid sebaceous gland carcinoma, and proposes that ABT-263 or a pharmaceutically acceptable salt thereof is used for preparing the medicine for treating the eyelid sebaceous gland carcinoma, the molecular formula of the ABT-263 is C 47 H 55 ClF3N5O6S3, and a molecular structure is shown as formula (I). The application further provides a medicine composition, which comprises a therapeutically effective amount of ABT-263 or a pharmaceutically acceptable salt thereof, and can be prepared into injection, emulsion, tablet, powder, granule, paste, liposome or oral liquid, in particular, a small-molecule injection preparation. It is found by the application that the ABT-263 can significantly inhibit the growth of eyelid sebaceous gland carcinoma cells, and the drug effect increases with the increase of concentration, so that the ABT-263 used for treating the eyelid sebaceous gland carcinoma can improve the treatment effectiveness, prolong the life of a patient, improve the quality of life, and has important clinical application value.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, and specifically relates to the application of a Bcl-xL, Bcl-2 and Bcl-w inhibitor in the preparation of a drug for treating eyelid sebaceous gland carcinoma. Background Technology

[0002] Eyelid sebaceous carcinoma (SeC), the third most common malignant tumor of the eyelid worldwide, has a particularly high incidence in Asian populations, accounting for nearly 40% of all eyelid malignancies in China. This cancer primarily originates from the meibomian glands, Zeis glands, and periocular skin. Its unique biological characteristics give it a high risk of metastasis, easily spreading to regional lymph nodes and distant organs, resulting in a disease-specific mortality rate ranging from 1.6% to 31.0%. Although complete surgical resection of the tumor is the standard treatment for eyelid SeC, the diffuse growth pattern and lack of well-defined boundaries of some tumors make complete resection extremely challenging, especially for patients with distant metastases who often cannot tolerate surgery due to deteriorating physical condition. Therefore, finding an effective treatment for aggressive, progressive, and poorly differentiated eyelid SeC has become an urgent clinical need.

[0003] Currently, there is a lack of effective drug treatment for this tumor. Navitoclax (ABT-263) is a Bcl-xL, Bcl-2, and Bcl-w inhibitor, but there are no reports to date of its use in eyelid sebaceous gland carcinoma, and its efficacy and mechanism of action in eyelid sebaceous gland carcinoma are still unclear. Summary of the Invention

[0004] To overcome the above-mentioned shortcomings of the prior art, the purpose of this invention is to provide the application of Bcl-xL, Bcl-2 and Bcl-w inhibitors in the preparation of drugs for treating eyelid sebaceous gland carcinoma, providing a new treatment approach for aggressive, progressive and poorly differentiated eyelid SeC.

[0005] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0006] This invention provides the use of Bcl-xL, Bcl-2, and Bcl-w inhibitors in the preparation of a medicament for treating eyelid sebaceous gland carcinoma, wherein the Bcl-xL, Bcl-2, and Bcl-w inhibitors are Navitoclax (ABT-263) or a pharmaceutically acceptable salt thereof, and the molecular formula of ABT-263 is C1. 47 H 55 ClF3N5O6S3, the molecular structure is shown in formula (I):

[0007]

[0008] Preferably, the pharmaceutically acceptable salt of ABT-263 is selected from one or more combinations of hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid, or benzenesulfonate.

[0009] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of ABT-263 or a pharmaceutically acceptable salt thereof, wherein the molecular formula of ABT-263 is C2. 47 H 55 ClF3N5O6S3 has a molecular structure as shown in formula (I).

[0010] Preferably, the concentration of ABT-263 in the pharmaceutical composition is 1-100 μM.

[0011] More preferably, the concentration of ABT-263 in the pharmaceutical composition is 1-10 μM.

[0012] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient, and can be prepared as an injection, emulsion, tablet, powder, granule, ointment, liposome, or oral liquid.

[0013] This invention also provides a small molecule injectable formulation comprising a therapeutically effective amount of ABT-263 or a pharmaceutically acceptable salt thereof, wherein the molecular formula of ABT-263 is C2. 47 H 55 ClF3N5O6S3 has a molecular structure as shown in formula (I).

[0014] Preferably, the small molecule injectable formulation uses ABT-263 or a pharmaceutically acceptable salt thereof as the active ingredient at a concentration of 1-100 μM.

[0015] More preferably, the concentration of ABT-263 in the small molecule injection is 1-10 μM.

[0016] Compared with existing technologies, this invention is the first to discover that Navitoclax (ABT-263), an inhibitor of Bcl-xL, Bcl-2, and Bcl-w, can significantly inhibit the growth of eyelid sebaceous gland cancer cells, and the drug's effect increases with increasing concentration. This provides a new therapeutic drug for the clinical treatment of eyelid sebaceous gland cancer, improves treatment effectiveness, prolongs patient life, improves quality of life, and opens up a new field for the treatment of eyelid sebaceous gland cancer with ABT-263, which has important clinical application value. Attached Figure Description

[0017] Figure 1The molecular structure of ABT-263.

[0018] Figure 2 The results are from the plate cloning experiment in Example 1.

[0019] Figure 3 The results are from the cell proliferation experiment (CCK8) in Example 2. Detailed Implementation

[0020] The present invention will be further described below with reference to the embodiments:

[0021] Example 1

[0022] Plate cloning experiment

[0023] Materials: Eyelid sebaceous gland cancer cell line SHNPH-SeC, trypsin, and PBS were purchased from Gibco; ABT263 was purchased from Selleck (structural formula shown below). Figure 1 (As shown), the crystal violet was purchased from Beyotime.

[0024] Procedure: Select the SHNPH-SeC eyelid sebaceous gland cancer cell line in logarithmic growth phase and good condition. When the cells reach approximately 70-80% confluence, digest them with trypsin. Count the digested cells using a cell counting chamber and seed them into 6-well plates, ensuring each well contains 2 mL of culture medium, 1000 cells, and ABT-263 at concentrations of 0, 0.5, 1, and 2 μL respectively. Due to the relatively small cell requirement, the volume of cell suspension added is very small. First, dilute the cells to 10000 / mL, then add 10 μL of the cell suspension. Then, incubate at 37°C in a 5% CO2 cell culture incubator for one week (observe clone size; terminate culture when most clone clusters reach more than 50 cells). Aspirate the culture medium, wash with PBS, add crystal violet and stain for 30 min, wash away excess crystal violet dye with PBS, photograph and observe the results. One group is formed per well, with three replicates per group. Results are shown below. Figure 2 As shown.

[0025] Example 2

[0026] Cell proliferation assay (CCK8)

[0027] Materials: The eyelid sebaceous gland cancer cell line SHNPH-SeC, trypsin, and PBS were purchased from Gibco, ABT263 was purchased from Selleck, and the CCK8 kit was purchased from Selleck.

[0028] Procedure: Select the SHNPH-SeC eyelid sebaceous gland cancer cell line in logarithmic growth phase and good condition. Digest with trypsin, centrifuge at 800 rpm, discard the supernatant, add fresh culture medium, and count the cells using an electronic cell counting chamber. Seed the cells at a density of 3000 cells / well in a 96-well cell culture plate with 100 μL of culture medium per well. A drug concentration gradient of 0, 0.5, 1, and 2 μL of ABT-263 was set, with 3 replicates. Before seeding, thoroughly mix the cell suspension to ensure the same total cell count and drug concentration in each well. Set 5 time points: 0 h, 24 h, 48 h, 72 h, and 96 h. The seeding time point for the selected wells was set as 0 h. After adding 10 μL of CCK8 reagent, incubate at 37°C in a 5% CO2 incubator in the dark for 4 h. Remove the culture plate and measure the absorbance at 450 nm using a microplate reader. Detect the growth every 24 hours, then return the culture plate to the incubator. Avoid generating air bubbles during the experiment to prevent interference with the microplate reader readings. Use GraphPad software to plot the growth curve. Results are shown below. Figure 3 As shown.

[0029] In conclusion, ABT-263 can significantly inhibit the growth of eyelid sebaceous gland cancer cells, and the drug effect increases with increasing concentration, proving that it can be used for the treatment of eyelid sebaceous gland cancer and providing a new therapeutic drug for clinical treatment.

[0030] The above description represents a preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, any equivalent or modified versions made without departing from the spirit of the present invention fall within the scope of protection of the present invention.

Claims

1. The use of a Bcl-xL, Bcl-2, and Bcl-w inhibitor in the preparation of a medicament for treating eyelid sebaceous gland carcinoma, wherein the Bcl-xL, Bcl-2, and Bcl-w inhibitor is ABT-263 or a pharmaceutically acceptable salt thereof, the molecular formula of ABT-263 being C 47 H 55 ClF3N5O6S3, the molecular structure is shown in formula (I):

2. The application according to claim 1, characterized in that, The pharmaceutically acceptable salt of ABT-263 is selected from one or more combinations of hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid, or benzenesulfonate.

3. A pharmaceutical composition, characterized in that, It contains a therapeutically effective amount of ABT-263 or a pharmaceutically acceptable salt thereof, wherein the molecular formula of ABT-263 is C 47 H 55 ClF3N5O6S3 has a molecular structure as shown in formula (I).

4. The pharmaceutical composition according to claim 3, characterized in that, The concentration of ABT-263 or its pharmaceutically acceptable salt is 1-100 μM.

5. The pharmaceutical composition according to claim 4, characterized in that, The concentration of ABT-263 or its pharmaceutically acceptable salt is 1-10 μM.

6. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient, and can be prepared as an injection, emulsion, tablet, powder, granule, ointment, liposome, or oral liquid.

7. A small molecule injectable formulation, characterized in that, It contains a therapeutically effective amount of ABT-263 or a pharmaceutically acceptable salt thereof, with ABT-263 or a pharmaceutically acceptable salt thereof as the active ingredient, at a concentration of 1-100 μM, wherein the molecular formula of ABT-263 is C 47 H 55 ClF3N5O6S3 has a molecular structure as shown in formula (I).

8. The small molecule injectable formulation according to claim 7, characterized in that, The concentration of ABT-263 or its pharmaceutically acceptable salt is 1-10 μM.

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