Use of mitoxantrone in preparation of drug, and method for treating or preventing neuroendocrine tumor

Abstract

Disclosed are a use of Mitoxantrone or an isomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt thereof, a prodrug thereof, or a derivative thereof in the preparation of a drug for treating or preventing neuroendocrine tumor, and a method for treating or preventing neuroendocrine tumor. Research shows that Mitoxantrone can inhibit the growth of neuroendocrine tumor in a dose-dependent manner, has high drug sensitivity and significant tumor inhibition effect, is a new candidate drug for the clinical treatment of neuroendocrine tumor, and has high clinical value.

Description

Use of mitoxantrone in the manufacture of a medicament, a method of treating or preventing neuroendocrine tumors TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to the use of Mitoxantrone or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, prodrugs or derivatives thereof in the manufacture of a medicament for treating or preventing neuroendocrine tumors, a method of treating or preventing neuroendocrine tumors. BACKGROUND

[0002] Neuroendocrine tumors are a group of heterogeneous tumors originating from neuroendocrine cells, which are distributed throughout multiple organs of the body, including the lung, gastrointestinal tract, and pancreas. According to the latest release of the SEER database, the global incidence of neuroendocrine tumors is 6.98 / 100,000 per year, of which gastrointestinal pancreatic neuroendocrine tumors account for about 3.56 / 100,000, accounting for 51%, and the top three are lung, small intestine, and rectum. Although neuroendocrine tumors as a whole grow slowly, certain types of neuroendocrine tumors, such as the neuroendocrine subtype in small cell lung cancer, exhibit high invasiveness and poor prognosis.

[0003] Current treatment methods for neuroendocrine tumors mainly include surgery, drug therapy (such as somatostatin analogs, targeted therapy, chemotherapy, biological therapy), radiotherapy, interventional therapy, and supportive therapy, forming a multidimensional comprehensive treatment strategy. Although these methods have alleviated symptoms, controlled tumor growth, and even prolonged patient survival to some extent, existing treatments still face many challenges. For example, surgery is not suitable for all patients, especially for advanced metastatic patients; in drug therapy, chemotherapy has limited efficacy on neuroendocrine tumors and significant side effects; targeted therapy and immunotherapy show some promise, but response rates and durability vary significantly among different patients; and small molecule drugs, with their unique structural characteristics, can more effectively penetrate cell membranes and target specific molecular targets within tumor cells, such as abnormally activated signaling pathways, thereby improving treatment efficiency while reducing damage to normal tissues. This high degree of specificity and lower systemic toxicity makes small molecule drugs an important direction for improving the precision of neuroendocrine tumor treatment and the quality of life of patients. Therefore, developing small molecule drugs for neuroendocrine tumors has positive clinical value.

[0004] Mitoxantrone 2HCl is an FDA-approved anti-tumor drug, belonging to the anthracycline class of chemotherapy drugs. It has significant anti-tumor activity, interfering with nucleic acid synthesis by embedding in DNA structure, causing DNA damage and inhibiting the activity of topoisomerase II, thereby exerting cytotoxic effects, inhibiting the growth and division of tumor cells. In clinical practice, Mitoxantrone 2HCl is approved for the treatment of various types of cancer, including acute myeloid leukemia (AML), breast cancer, non-Hodgkin's lymphoma (NHL), etc. Although Mitoxantrone 2HCl can be used as a broad-spectrum anti-tumor drug in theory, its therapeutic effect in neuroendocrine tumors has not been reported.

[0005] SUMMARY

[0006] The present application is based on the inventors' discovery and understanding of the following problems:

[0007] The inventors found through in vitro and in vivo experiments that Mitoxantrone 2HCl can inhibit the growth and proliferation of neuroendocrine cervical cancer organoids in vitro in a dose-dependent manner, and can completely kill neuroendocrine cervical cancer organoids at working concentrations of 10 μM, 1 μM, and 0.1 μM, with an IC 50 less than 10 nM, showing extremely high drug sensitivity. Further in vivo validation experiments in mice showed that Mitoxantrone 2HCl can effectively inhibit the growth of neuroendocrine cervical cancer organoid transplanted tumors in mice, and its effect is more significant than that of conventional chemotherapy drugs. The above results show that Mitoxantrone or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, its prodrugs or derivatives thereof are new candidate drugs for the clinical treatment of neuroendocrine tumors, especially neuroendocrine cervical cancer, with high clinical value.

[0008] Therefore, in a first aspect of the present application, the present application provides the use of Mitoxantrone or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, its prodrugs or derivatives thereof in the preparation of a medicament for treating or preventing neuroendocrine tumors. According to embodiments of the present application, Mitoxantrone can inhibit the growth of neuroendocrine tumors in a dose-dependent manner, has high drug sensitivity, significant tumor inhibition effect, is a new candidate drug for the clinical treatment of neuroendocrine tumors, and has high clinical value.

[0009] According to embodiments of the present application, the neuroendocrine tumor originates from at least one of a lung neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal cavity neuroendocrine cell, a laryngeal neuroendocrine cell, a kidney neuroendocrine cell.

[0010] According to embodiments of the present application, the neuroendocrine tumor is at least one of a lung neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal cavity neuroendocrine tumor, a laryngeal neuroendocrine tumor, a kidney neuroendocrine tumor.

[0011] According to embodiments of the present application, the neuroendocrine tumor is a neuroendocrine cervical cancer. Neuroendocrine cervical cancer is a rare subtype of cervical cancer, originating from cervical neuroendocrine cells, accounting for less than 5% of all cervical cancers, and usually has higher invasiveness and poor response to traditional cervical cancer treatment methods. According to embodiments of the present application, Mitoxantrone has more significant efficacy on neuroendocrine cervical cancer than conventional chemotherapy drugs, and can significantly inhibit tumor growth in animals.

[0012] According to embodiments of the present application, the pharmaceutically acceptable salt of Mitoxantrone is at least one of Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate.

[0013] According to embodiments of the present application, the pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone hydrochloride.

[0014] According to embodiments of the present application, the pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone 2HCl.

[0015] In a second aspect of the present application, a method for treating or preventing a neuroendocrine tumor is provided. According to embodiments of the present application, the method comprises administering a pharmaceutically acceptable amount of Mitoxantrone or its isomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts, prodrugs thereof, or derivatives thereof to a subject.

[0016] According to embodiments of the application, the neuroendocrine tumor originates from at least one of a lung neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal gland neuroendocrine cell, a cervical neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal cavity neuroendocrine cell, a laryngeal neuroendocrine cell, a kidney neuroendocrine cell.

[0017] According to some optional embodiments of the application, the neuroendocrine tumor is at least one of a lung neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal gland neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal cavity neuroendocrine tumor, a laryngeal neuroendocrine tumor, a kidney neuroendocrine tumor.

[0018] According to embodiments of the application, the neuroendocrine tumor is a neuroendocrine cervical cancer.

[0019] According to embodiments of the application, the Mitoxantrone pharmaceutically acceptable salt is at least one of Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate.

[0020] According to embodiments of the application, the Mitoxantrone pharmaceutically acceptable salt is Mitoxantrone hydrochloride.

[0021] According to embodiments of the application, the Mitoxantrone pharmaceutically acceptable salt is Mitoxantrone 2HC1.

[0022] Additional aspects and advantages of the application will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following and / or by practice of the application. BRIEF DESCRIPTION OF DRAWINGS

[0023] The above and / or additional aspects and advantages of the application will become apparent and be more readily understood from the following description, taken in conjunction with the accompanying drawings, in which:

[0024] Figure 1 is a bright field image of neuroendocrine cervical cancer organoids treated with different working concentrations of Mitoxantrone 2HCl in Example 1 of the present application, wherein, from top to bottom, the organoids treated with control group (Control), 10 μM, 1 μM, 0.1 μM working concentration, from left to right are three wells, scale bar 200 μm;

[0025] Figure 2 is a graph showing the results of cell viability analysis of neuroendocrine cervical cancer organoids treated with different working concentrations of Mitoxantrone 2HCl in Example 1 of the present application;

[0026] Figure 3 is an IC 50 curve graph showing the inhibitory effect of Mitoxantrone 2HCl on neuroendocrine cervical cancer organoids in Example 2 of the present application;

[0027] Figure 4 is a bright field image of tumor tissue of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Mitoxantrone 2HCl in Example 3 of the present application;

[0028] Figure 5 is a graph showing the results of tumor volume analysis of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Mitoxantrone 2HCl in Example 3 of the present application;

[0029] Figure 6 is a graph showing the results of tumor weight analysis of neuroendocrine cervical cancer organoids after subcutaneous tumor formation in mice and treatment with Mitoxantrone 2HCl in Example 3 of the present application. DETAILED DESCRIPTION

[0030] The embodiments of the present application are described in detail below. The embodiments described below are exemplary only, and are not to be construed as limiting the present application.

[0031] It should be noted that the terms "first", "second" are used only for the purpose of description, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the technical features indicated. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, unless otherwise specified, the meaning of "a plurality of" is two or more.

[0032] In this document, the term "Mitoxantrone" is equivalent to "Mitoxantrone", which has the chemical structure as shown below:

[0033] Salts of Mitoxantrone, generally have improved drug solubility and stability, facilitating drug formulation and administration. In practical applications, the salt form of a drug does not change its basic pharmacological action. Common salt forms of Mitoxantrone, including but not limited to: Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate.

[0034] In this context, the term "Mitoxantrone 2HCI" is equivalent to "Mitoxantrone dihydrochloride", is the most common form of Mitoxantrone.

[0035] In this context, the term "Neuroendocrine Neoplasms" is equivalent to "NENs", is a group of relatively rare tumors that originate from neuroendocrine cells in various parts of the body. These cells have the ability to secrete hormones, which can produce peptide hormones and biogenic amines, etc. Neuroendocrine tumors can be benign or malignant, and malignant neuroendocrine tumors can invade surrounding tissues or metastasize to distant organs. These neuroendocrine tumors all originate from neuroendocrine cells, which have both neural and endocrine properties, and can produce and secrete hormones and other bioactive substances. Neuroendocrine tumors are classified according to their origin, including but not limited to neuroendocrine tumors originating from lung neuroendocrine cells, gastrointestinal neuroendocrine cells, pancreatic neuroendocrine cells, adrenal neuroendocrine cells, cervical neuroendocrine cells, adrenal neuroendocrine cells, thyroid neuroendocrine cells, pituitary neuroendocrine cells, liver neuroendocrine cells, skin neuroendocrine cells, breast neuroendocrine cells, nasal neuroendocrine cells, laryngeal neuroendocrine cells, kidney neuroendocrine cells. Common neuroendocrine tumors include lung neuroendocrine tumors, gastrointestinal neuroendocrine tumors, pancreatic neuroendocrine tumors, adrenal neuroendocrine tumors, neuroendocrine cervical cancer, thyroid neuroendocrine tumors, pituitary neuroendocrine tumors, liver neuroendocrine tumors, skin neuroendocrine tumors, breast neuroendocrine tumors, nasal neuroendocrine tumors, laryngeal neuroendocrine tumors, kidney neuroendocrine tumors. Although these tumors occur in different organs and tissues, they are similar in biological behavior and treatment strategies.

[0036] Neuroendocrine cervical cancer originates from neuroendocrine cells of the cervix, which are capable of producing hormones and other bioactive substances. In the embodiments of the present application, neuroendocrine cervical cancer is selected as a representative disease of neuroendocrine tumors, and the therapeutic effect of the chemotherapeutic drug Mitoxantrone on neuroendocrine tumors is investigated, so as to provide more clinical drug selection for patients.

[0037] In the present text, the term "treatment" refers to obtaining a desired pharmacological and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete cure of a disease and / or adverse effect attributable to the disease. "Treatment" as used herein covers the treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or condition from occurring in an individual which can be predisposed to the disease but has not yet developed the disease; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing the partial or complete regression of the symptoms of the disease. "Treatment" as used herein covers any use of a drug or product in an individual to treat, cure, relieve, alleviate, improve, lessen or inhibit a disease in the individual, including but not limited to administering a drug containing the drug described herein to an individual in need thereof.

[0038] In the present text, the term "prevention" is used to refer to an attempt to terminate the appearance of a disease or condition before it occurs.

[0039] It should be noted that the terms "subject", "individual" and "patient" are used interchangeably herein and refer to a mammal being evaluated for treatment and / or being treated. In one embodiment, the mammal is a human. The terms "subject", "individual" and "patient" include, but are not limited to, a patient having a neuroendocrine tumor, such as an individual having neuroendocrine cervical cancer. The subject can be a human, but also includes other mammals, particularly mammals useful as laboratory models of human disease, e.g., mice, rats, etc.

[0040] In the present text, the term "pharmaceutically acceptable amount" is an amount suitable for use in humans and / or mammals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio, i.e., the amount of a substance which is acceptable to those of ordinary skill in the art for use in humans and / or animals.

[0041] In the present context, the term "administration" is equivalent to "dosing" and refers to the introduction of a predetermined amount of a substance into a patient by some suitable means. The aforementioned drug can be dosed by any common route, provided it reaches the intended tissue. Various modes of administration are contemplated, including intraperitoneal, intravenous, intramuscular, subcutaneous, and the like, but the present application is not limited to these exemplified modes of administration. The effective amount of the aforementioned drug can vary depending on the mode of administration and the severity of the disease to be treated, etc. Preferably, the effective amount can be determined by one of ordinary skill in the art (e.g., through clinical trials) based on various factors. The factors include, but are not limited to, pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the body weight of the patient, the immune status of the patient, the route of administration, etc. For example, several divided doses can be administered daily, or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[0042] As used herein, the term "effective amount" or "effective dose" refers to an amount that produces a function or activity in and / or is acceptable to a human and / or animal.

[0043] The scheme of the present application will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustrating the present application and should not be considered as limiting the scope of the present application. The experimental methods in the following examples are routine methods unless otherwise specified. The reagents or instruments involved in the present application are not specified by the manufacturer, and are all commercially available in the market.

[0044] Example 1: Mitoxantrone 2HC1 significantly inhibits the proliferation of neuroendocrine cervical cancer organoids in vitro

[0045] In this example, the neuroendocrine cervical cancer organoids were constructed from tumor cells isolated from patient neuroendocrine cervical cancer tissue. Based on this, if the aforementioned human neuroendocrine tumor cells are obtained by isolating patient tumor tissue, the research involving the use of human tissue must comply with government laws and regulations of all relevant agencies, and the informed consent of the patient must be obtained before the tissue is taken and tested. In this example, the method for investigating the significant inhibitory effect of Mitoxantrone 2HC1 on the proliferation of neuroendocrine cervical cancer organoids in vitro is as follows:

[0046] The organoids that have been successfully constructed and amplified in the culture plates were digested into single cells, and the number of cells in the suspension was measured. The cells were resuspended in extracellular matrix at a density of 3000 cells / μL;

[0047] 3 μL of the mixture of cell clusters and extracellular matrix was added to each well of a 96-well plate, and 100 μL of culture medium was added to each well. The plate was incubated in a 37°C incubator;

[0048] After 5 days of culture, different concentrations (10, 1, 0.1 μM) of Mitoxantrone 2HCl were added, and the control group was added with the same proportion of DMSO dilution, and continued to be cultured in a 37°C incubator;

[0049] After 5 days of drug culture, the culture medium was replaced with organoid cell activity detection reagent, and the fluorescence intensity (FI) at excitation wavelength 560 nm and emission wavelength 590 nm was measured after 37°C incubation for 30 min. At the same time, imaging was performed for each well using Cytation5 multifunctional cell imaging microplate detector, and the inhibitory effect of Mitoxantrone 2HCl on neuroendocrine cervical cancer organoids was determined according to the above results.

[0050] The inhibitory effect of different concentrations of Mitoxantrone 2HCl on neuroendocrine cervical cancer organoids is shown in Figures 1 and 2.

[0051] The results show that, compared with the control group (Control), the viability of neuroendocrine cervical cancer organoids treated with Mitoxantrone 2HCl at 10 μM, 1 μM, and 0.1 μM working concentrations is less than 1%. This indicates that Mitoxantrone 2HCl has a strong inhibitory effect on neuroendocrine cervical cancer organoids at these three concentrations.

[0052] Example 2: Mitoxantrone 2HCl inhibits neuroendocrine cervical cancer organoids in a dose-dependent manner

[0053] The successfully constructed and massively amplified organoids in the culture plates were digested into single cells, and the number of cells in the suspension was measured. The cells were resuspended in extracellular matrix at a density of 3000 cells / μL;

[0054] 3 μL of the mixture of cell clusters and extracellular matrix was added to each well of the 96-well plate, and 100 μL of culture medium was added to each well. The plates were incubated in a 37°C incubator.

[0055] After 5 days of culture, 7 Mitoxantrone 2HCl drug concentration gradients were set according to a 10-fold gradient, with a concentration range of 0.0003 nM-300 nM. The control group was added with the same proportion of DMSO dilution, and continued to be cultured in a 37°C incubator.

[0056] After 5 days of drug culture, the culture medium was replaced with organoid cell activity detection reagent, and the fluorescence intensity (FI) at excitation wavelength 560 nm and emission wavelength 590 nm was measured after 37°C incubation for 30 min. According to the above results, the IC of Mitoxantrone 2HCl on neuroendocrine cervical cancer organoids was determined.50 Curve.

[0057] IC of Mitoxantrone 2HCl on neuroendocrine cervical cancer organoids 50 The curve is shown in Figure 3.

[0058] The results show that Mitoxantrone 2HCl inhibits neuroendocrine cervical cancer organoids in a dose-dependent manner; its IC 50 is less than 10 nM, indicating that neuroendocrine cervical cancer organoids are highly sensitive to Mitoxantrone 2HCl.

[0059] Example 3: Mitoxantrone 2HCl significantly inhibits the growth of neuroendocrine cervical cancer organoid xenografts in vivo

[0060] Three 6-week-old, 18-24 g immunodeficient mice of BALB / c-Nude strain were selected for subcutaneous transplantation of neuroendocrine cervical cancer organoids, and each mouse was transplanted with 2 x 10 6 cells of organoids, and when the tumor volume reached 800-1000 mm 3 , the mice were sacrificed, the tumor tissue was dissected, and after removing the capsule and necrotic part, the tissue was cut into 2 mm 3 tissue fragments.

[0061] Eighteen 6-week-old, 18-24 g immunodeficient mice of BALB / c-Nude strain were selected for subcutaneous transplantation of neuroendocrine cervical cancer tissue, and each mouse was transplanted with 2 pieces of 2 mm 3 tumor tissue fragments, and when the average tumor volume reached 100-200 mm 3 , the mice were randomly divided into three groups for treatment, including a blank control group (normal saline treatment group, i.e., Control group), a positive control group (paclitaxel and carboplatin combined treatment group, i.e., Paclitaxel + Carboplatin), and an experimental group (Mitoxantrone 2HCl treatment group), with 6 mice in each group. The mice in the blank control group were treated with intraperitoneal injection of normal saline once a week, with an injection volume of 100-200 μL per mouse (same volume as the experimental group); the mice in the positive control group were treated with intraperitoneal injection of a mixture of paclitaxel and carboplatin once a week, with injection doses of 10 mg / kg per mouse and 50 mg / kg per mouse, respectively; the mice in the experimental group were treated with tail vein injection of Mitoxantrone 2HCl every three days, with an injection dose of 10 mg / kg per mouse. The experiment was terminated when the tumor volume of the mice in the blank control group exceeded 2000 mm 3 . The tumor volume was measured using a vernier caliper, and the tumor volume was calculated as V = a 2V = ab (where V is the volume, a is the length of the shortest side, and b is the length of the longest side).

[0062] The inhibitory effect of Mitoxantrone 2HCl on the growth of neuroendocrine cervical cancer in mice is shown in Figures 4, 5, and 6.

[0063] The results show that the tumor volume of the Mitoxantrone 2HCl treatment group is significantly reduced compared with the blank control group (Figures 4 and 5), the tumor weight is significantly reduced (Figure 6), and this inhibitory effect is more obvious than that of the positive control group, indicating that Mitoxantrone 2HCl can significantly inhibit the growth of neuroendocrine tumors, especially neuroendocrine cervical cancer, in vivo, and is more effective than the chemotherapeutic drugs used in clinical practice.

[0064] Although the embodiments of the present application have been shown and described above, it is to be understood that the above-described embodiments are exemplary, and are not to be construed as limiting the present application, and that those skilled in the art can make changes, modifications, substitutions, and variations to the above-described embodiments within the scope of the present application.

Claims

1. Use of Mitoxantrone or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for the treatment or prevention of a neuroendocrine tumor.

2. Use according to claim 1, characterized in that, The neuroendocrine tumor originates from at least one of a pulmonary neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal neuroendocrine cell, a laryngeal neuroendocrine cell, a renal neuroendocrine cell.

3. Use according to claim 1, characterized in that, The neuroendocrine tumor is at least one of a pulmonary neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal neuroendocrine tumor, a laryngeal neuroendocrine tumor, a renal neuroendocrine tumor.

4. Use according to claim 3, characterized in that, The neuroendocrine tumor is a neuroendocrine cervical cancer.

5. Use according to any one of claims 1 to 4, characterized in that, The pharmaceutically acceptable salt of Mitoxantrone is at least one of Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate.

6. Use according to claim 5, characterized in that, The pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone hydrochloride.

7. Use according to claim 5, characterized in that, The pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone 2HCI.

8. A method of treating or preventing a neuroendocrine tumor, characterized by, Comprising: administering to a subject a pharmaceutically acceptable amount of Mitoxantrone or its isomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, prodrug or derivative thereof.

9. The method of claim 8, wherein, The neuroendocrine tumor originates from at least one of a pulmonary neuroendocrine cell, a gastrointestinal neuroendocrine cell, a pancreatic neuroendocrine cell, an adrenal neuroendocrine cell, a cervical neuroendocrine cell, a thyroid neuroendocrine cell, a pituitary neuroendocrine cell, a liver neuroendocrine cell, a skin neuroendocrine cell, a breast neuroendocrine cell, a nasal neuroendocrine cell, a laryngeal neuroendocrine cell, a renal neuroendocrine cell.

10. The method of claim 8, wherein, The neuroendocrine tumor is at least one of a pulmonary neuroendocrine tumor, a gastrointestinal neuroendocrine tumor, a pancreatic neuroendocrine tumor, an adrenal neuroendocrine tumor, a neuroendocrine cervical cancer, a thyroid neuroendocrine tumor, a pituitary neuroendocrine tumor, a liver neuroendocrine tumor, a skin neuroendocrine tumor, a breast neuroendocrine tumor, a nasal neuroendocrine tumor, a laryngeal neuroendocrine tumor, a renal neuroendocrine tumor.

11. The method of claim 10, wherein, The neuroendocrine tumor is a neuroendocrine cervical cancer. The pharmaceutically acceptable salt of Mitoxantrone is at least one of Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate. The pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone hydrochloride. The pharmaceutically acceptable salt of Mitoxantrone is Mitoxantrone 2HCI.

12. The method according to any one of claims 8 to 11, characterized in that, The Mitoxantrone pharmaceutically acceptable salt is selected from at least one of Mitoxantrone hydrochloride, Mitoxantrone oxalate, Mitoxantrone sulfate, Mitoxantrone phosphate, Mitoxantrone acetate, Mitoxantrone citrate.

13. The method of claim 12, wherein, The Mitoxantrone pharmaceutically acceptable salt is Mitoxantrone hydrochloride.

14. The method of claim 12, wherein, The Mitoxantrone pharmaceutically acceptable salt is Mitoxantrone 2HCl.

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