Use of abametapir in preparing antitumor drug

Abstract

Abametapir or a pharmaceutically acceptable salt thereof has antitumor activity and significant antitumor effects on gynecological tumors, digestive tract tumors, lung tumors, lymphomas, and the like. Abametapir has a significant inhibitory effect on the growth and development of various human tumor cells and tumors in tumor-bearing mice, and especially has a good inhibitory effect on triple-negative breast cancer. Abametapir or the pharmaceutically acceptable salt thereof has an effective antitumor effect by means of oral administration.

Description

Application of abamectin in the preparation of anti-tumor drugs Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the anti-tumor activity of abamectin and a new use thereof. Background Art

[0002] Cancer is a major global health challenge, severely impacting human health and well-being. According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. In 2022, there were nearly 20 million new cases of cancer worldwide, and 9.74 million cancer-related deaths. Although advances in molecular targeted therapy, immunotherapy, and cell therapy over the past two to three decades have expanded the range of cancer treatment options and significantly improved survival rates for some cancer patients, treatment outcomes for many tumor types remain unsatisfactory due to the diverse tissue origins, pathological and molecular characteristics of tumors, and individual variability, as well as the emergence of drug resistance. Therefore, there remains a significant clinical need for the research and development of new anti-cancer drugs. Compared to the traditional drug discovery and development approach, clinical repositioning of existing drugs to develop new clinical indications is a more cost-effective, efficient, and rapid new drug development strategy.

[0003] Abametapir, chemical name is 5 5'-dimethyl-2,2'-bipyridine, molecular formula is: C 12 H 12 N2, molecular weight 184.24, CAS number: 1762-34-1, chemical structure is as follows:

[0004]

[0005] Abamexazole is a white to pale yellow, non-hygroscopic solid. It is insoluble in water but soluble in acetonitrile, diethyl ether, dimethyl sulfoxide, isopropyl alcohol, and propylene glycol. It is freely soluble in acetic acid, acetone, benzene, benzyl alcohol, chloroform, dimethylformamide, dioxane, ethanol, methanol, ethyl acetate, and tetrahydrofuran, and slightly soluble in ethane, petroleum ether, and isopropyl alcohol. In July 2020, the U.S. Food and Drug Administration (FDA) approved Reddy's Laboratories' 0.74% abamexazole topical solution (trade name Xeglyze) for the treatment of head lice infestations in patients 6 months of age and older. Abamexazole is a metalloproteinase inhibitor that chelates heavy metal ions, targeting metalloproteinases involved in egg hatching and lice development, thereby killing lice eggs. Summary of the Invention

[0006] Our research group conducted drug repositioning research on abamexil, and the present invention provides the pharmacological effects of abamexil.

[0007] The purpose of the present invention is achieved through the following measures:

[0008] A new use of abamectin or its pharmaceutically acceptable salts in the preparation of drugs for treating or preventing tumors or cancers. We have discovered for the first time that abamectin has significant and broad anti-tumor activity, inhibiting the growth of various human tumor cells cultured in vitro.

[0009] Preferably, the above-mentioned tumor includes a solid tumor or a hematological tumor, specifically including a gynecological tumor, a digestive tract tumor, a lung tumor or a lymphoma, etc. More preferably, the tumor includes breast cancer, ovarian cancer, colorectal cancer, lung cancer or B-cell lymphoma, etc.

[0010] More preferably, abamectin and its pharmaceutically acceptable salts are used in the preparation of novel therapeutics and preventions for triple-negative breast cancer. Triple-negative breast cancer (TNBC) is a type of breast cancer characterized by negative estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. It is highly invasive and has a high incidence. Low concentrations of abamectin have a significant inhibitory effect on TNBC.

[0011] The maximum inhibitory concentration (IC50) of abamectin for inhibiting tumor cell proliferation can reach 13.3µmol / L; it has significant inhibitory activity on tumor growth in two triple-negative breast cancer model mice, 4T1 and EMT-6 (P<0.05 or P<0.01 compared with the vehicle control group).

[0012] An anti-tumor drug comprising the above-mentioned abamectin or a pharmaceutically acceptable salt thereof.

[0013] The drug is administered by any suitable route, such as oral administration, intravenous administration, intratumoral administration, or subcutaneous injection, etc. Preferably, the dose of abamectin is 50-100 mg / kg / day.

[0014] As a further optimization of the above solution, the drug is in an oral dosage form, including but not limited to tablets, capsules, oral solutions, dripping pills, granules, syrups, dispersible tablets, chewable tablets, and orally disintegrating tablets. Beneficial effects

[0015] The present invention discovers and discloses for the first time the anti-tumor activity of abamexyl, and the activity exhibits a broad-spectrum anti-tumor characteristic.

[0016] This invention, for the first time, demonstrates the broad and potent anti-tumor activity of abamexazole, demonstrating its significant anti-tumor effects against gynecological tumors, gastrointestinal tumors, lung tumors, and lymphomas. Experiments confirm that abamexazole significantly inhibits the growth and progression of various human tumor cells, as well as breast cancer-bearing mice. In in vitro experiments, abamexazole demonstrated significant inhibition of the proliferation of various cultured human tumor cells. Its IC50 values ​​for inhibition of proliferation in human breast cancer cells (MCF-7), human ovarian cancer cells (SK-OV-3), human colorectal cancer cells (COLC-205), human lung cancer cells (A549), and human B lymphocytes (SU-DHL-16) were 13.3µmol / L, 32.5µmol / L, 34.8µmol / L, 27.5µmol / L, and 29.9µmol / L, respectively. Abamexazole exhibited the strongest inhibitory effect against MCF-7 cells. In in vivo experiments, abamectin showed significant inhibitory effects on tumor growth in two tumor models established by subcutaneous injection of triple-negative breast cancer cells 4T1 and EMT-6 in mice, and its oral effect was comparable to the effect of doxorubicin, a commonly used chemotherapy drug in the clinical treatment of triple-negative breast cancer.

[0017] The present invention proposes that abamexyl has an effective anti-tumor effect when administered orally, has good patient compliance, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows the concentration-effect curves of abamectin on the proliferation inhibition of human breast cancer MCF-7 cells and human ovarian cancer SK-OV-3 cells in vitro for 48 hours. As can be seen from the figure, abamectin has a significant inhibitory effect on the proliferation of human breast cancer cells and human ovarian cancer cells.

[0019] Figure 2 is a concentration-effect curve of abamectin acting on human colorectal cancer COLO-205 cells and human lung cancer A549 cells in vitro for 48 hours to inhibit the proliferation of these two tumor cells. It can be seen from the figure that abamectin has a significant inhibitory effect on the proliferation of human colorectal cancer cells and human lung cancer cells.

[0020] Figure 3 shows the concentration-effect curve of abamectin on the proliferation inhibition of human B-cell lymphoma SU-DHL-16 cells after 48 hours of in vitro treatment. As can be seen from the figure, abamectin has a significant inhibitory effect on the proliferation of human lymphoma cells.

[0021] Figure 4 shows the inhibitory effect of abamectin on tumor growth in mice bearing triple-negative breast cancer 4T1 cells after oral administration. Panel A shows the effect on tumor weight after 14 days of treatment, and Panel B shows the effect on tumor volume on days 6 and 14 of treatment. Panels A and B demonstrate that abamectin significantly inhibits tumor growth in mice bearing triple-negative breast cancer.

[0022] Figure 5 shows the inhibitory effect of abamectin on tumor growth in mice bearing triple-negative breast cancer EMT-6 cells following oral administration. Panel A shows the effect on tumor weight after 14 days of treatment, and Panel B shows the effect on tumor volume on days 6 and 14 of treatment. As shown in Panels A and B, abamectin significantly inhibits tumor growth in mice bearing triple-negative breast cancer.

[0023] Figure 6 shows a photograph of the tumors of mice in each group 14 days after intragastric administration of abamectin to mice bearing triple-negative breast cancer 4T1 cells. As can be seen from the figure, abamectin can significantly inhibit the growth of triple-negative breast cancer tumors in mice.

[0024] Figure 7 shows a photograph of the tumors of mice in each group 14 days after intragastric administration of abamectin to mice bearing triple-negative breast cancer EMT-6 cells. As can be seen from the figure, abamectin can significantly inhibit the growth of triple-negative breast cancer tumors in mice. DETAILED DESCRIPTION

[0025] The present invention will be further described below by means of specific examples, but these examples are only for illustration rather than limitation of the present invention.

[0026] Example 1 Inhibitory effect of abamectin on human tumor cell proliferation in vitro

[0027] Human breast cancer MCF-7 cells, human ovarian cancer cells SK-OV-3 cells, human colorectal cancer cells COLO-205 cells, human lung cancer cells A549 cells, and human B lymphocytes SU-DHL-16 cells were used. These cell lines were purchased from ATCC. Abamepyr was purchased from Shanghai Aladdin (Cat. No. GC46769) and diluted to 150 mM in dimethyl sulfoxide (DMSO). Each of the five cell types was seeded in a 384-well plate and incubated with abamepyr at final concentrations of 300,000, 100,000, 33333.3, 11111.1, 3703.7, 1234.6, 411.5, 137.2, 45.72, and 15.24 nM for 48 hours. Each concentration was set up in duplicate wells. Then, 30 μL of reagent (Promega, Celltiter Glo assay kit) was added to each well, shaken for 3 minutes in the dark, and allowed to stand at room temperature for 30 minutes before being placed in a microplate reader to read the chemiluminescence value.

[0028] The results are shown in Figures 1, 2 and 3. Abamectin showed significant proliferation inhibitory activity against five human tumor cell lines. The half-maximal inhibitory concentrations (IC50) for inhibiting the proliferation of human breast cancer cells MCF-7, human ovarian cancer cells SK-OV-3, human colorectal cancer cells COLO-205, human lung cancer cells A549 and human B lymphocytes SU-DHL-16 were 13.3µmol / L, 32.5µmol / L, 34.8µmol / L, 27.5µmol / L and 29.9µmol / L, respectively. The strongest inhibitory effect was on the proliferation of human breast cancer cells MCF-7.

[0029] Example 2 Effect of in vivo administration of abamectin on tumor growth of triple-negative breast cancer 4T1 cells in mice

[0030] Sixteen female Balb / c mice weighing 18-22 g and aged 6-8 weeks were used for the experiment. Abametazole (Cat. No. D154986, purity >98%) and doxorubicin (Cat. No. A183027, purity 97%) were purchased from Shanghai Aladdin Co., Ltd. The mouse triple-negative breast cancer cell line 4T1 was purchased from ATCC. 4T1 cells were cultured in RPMI-1640 medium and inoculated subcutaneously into the right axilla of the mice (5 x 10 6 After 7-10 days, the tumor grew to about 50 mm under the mouse skin. 3 The tumor-bearing mice were divided into the following groups: vehicle control group, doxorubicin group and abamectin group, with 5 mice in each vehicle control group and doxorubicin group, and 6 mice in the abamectin group. Among them, the doxorubicin group was intraperitoneally injected with a dose of 5 mg / kg, once every 3 days, for a total of 3 times. The abamectin group was gavaged with abamectin suspension at a dose of 100 mg / kg, once a day, for 14 consecutive days. The vehicle control group was gavaged with an equal amount of vehicle 0.5% sodium carboxymethyl cellulose solution, once a day, for 14 consecutive days. After administration, the general condition and body weight of the mice were monitored and recorded every day, and the tumor size was measured on the 6th day after administration. The mice were anesthetized with 3.5% chloral hydrate 24 hours after the last administration. The mice were killed and the tumor tissues were taken, the tumor size was measured, the tumor weight was weighed, and tumor photos were taken.

[0031] Preparation of doxorubicin solution: Weigh doxorubicin powder and dissolve in PBS to prepare a 10 mg / ml doxorubicin stock solution. Store at -20°C. Dilute with PBS to a 1 mg / ml application solution before administration, with a dosing volume of 5 ml / kg.

[0032] Preparation of 0.5% sodium carboxymethyl cellulose solution by mass concentration: weigh sodium carboxymethyl cellulose powder and disperse it in pure water preheated at 60°C in a water bath. Stir while adding until completely dissolved to form a solution with a mass concentration of 0.5%. Store at 4°C until used.

[0033] Preparation of abamexazole suspension: Weigh abamexazole powder, grind it evenly with a mill, disperse it into 0.5% sodium carboxymethylcellulose solution, dissolve it by ultrasonication, and prepare a 10 mg / ml abamexazole suspension. Prepare it and use it immediately each time, with a dosage volume of 10 ml / kg.

[0034] The experimental results are shown in Figures 4 and 6. It can be seen that oral (oral) administration of abamexazole to 4T1 triple-negative breast cancer mice can significantly inhibit the growth of breast cancer tumor volume and tumor weight. There is no significant difference in mouse body weight among the three groups. The inhibitory effect of oral (oral) administration of abamexazole on tumor growth is comparable to the therapeutic effect of doxorubicin injection.

[0035] Example 3 Effect of in vivo administration of abamectin on tumor growth of triple-negative breast cancer EMT-6 cells in mice

[0036] Twelve female Balb / c mice weighing 18-22 g and aged 6-8 weeks were used for the experiment. Abamid and doxorubicin were purchased from Shanghai Aladdin. The mouse triple-negative breast cancer cell line EMT-6 was purchased from ATCC. EMT-6 cells were cultured in RPMI-1640 medium and inoculated subcutaneously into the right axilla of the mice (5 x 10 6 After 7-10 days, the tumor grew to about 50 mm under the mouse skin. 3 Tumor-bearing mice were divided into vehicle control, doxorubicin, and abamectin groups. The vehicle control group consisted of five mice, the doxorubicin group consisted of three mice, and the abamectin group consisted of four mice. The doxorubicin group (drug concentration: 1 mg / ml, dosing volume: 5 ml / kg) was intraperitoneally injected at a dose of 5 mg / kg every three days for three doses. The abamectin group (drug concentration: 10 mg / ml, dosing volume: 10 ml / kg) was orally administered at a dose of 100 mg / kg once daily for 14 consecutive days. The vehicle control group was orally administered with an equal volume of a 0.5% sodium carboxymethylcellulose solution containing the vehicle mass once daily for 14 consecutive days. The general condition and body weight of the mice were monitored and recorded daily after dosing. Tumor size was measured on day 6 after dosing. Twenty-four hours after the last dose, the mice were anesthetized with 3.5% chloral hydrate and sacrificed. Tumor tissue was obtained, tumor size and weight were measured, and tumor photographs were taken.

[0037] The experimental results, shown in Figures 5 and 7, show that oral administration (or gavage) of abamexyl to mice bearing EMT-6 triple-negative breast cancer significantly inhibited the growth of breast cancer tumor volume and weight. Its tumor growth inhibition effect is comparable to that of doxorubicin.

Claims

1. A new use of abameprid or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing tumors or cancers.

2. The novel use according to claim 1, wherein the tumor comprises a solid tumor or a hematological tumor.

3. The novel use according to claim 1, wherein the tumor comprises a gynecological tumor, a digestive tract tumor, a lung tumor or a lymphoma.

4. The novel use according to any one of claims 1 to 3, wherein the tumor comprises breast cancer, ovarian cancer, colorectal cancer, lung cancer, or B-cell lymphoma.

5. The novel use according to claim 4, wherein the tumor is triple-negative breast cancer.

6. An antitumor drug comprising abamectin or a pharmaceutically acceptable salt thereof.

7. The drug according to claim 6, which is administered by any suitable route, such as oral administration, intravenous administration, intratumoral administration, or subcutaneous injection.

8. The drug according to claim 6 or 7, wherein the dosage of abamectil or a pharmaceutically acceptable salt thereof is 50-100 mg / kg / day.

9. The drug according to claim 6 or 7, wherein the dosage form includes tablets, capsules, oral solutions, dripping pills, granules, syrups, dispersible tablets, chewable tablets, orally disintegrating tablets and the like.

10. The drug according to claim 8, wherein the dosage form comprises tablets, capsules, oral solutions, dripping pills, granules, syrups, dispersible tablets, chewable tablets, orally disintegrating tablets and the like.

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