CN111643513A - Combination of aprepitant and cytarabine and anti-leukemia effect thereof - Google Patents
Combination of aprepitant and cytarabine and anti-leukemia effect thereof Download PDFInfo
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- CN111643513A CN111643513A CN202010484869.3A CN202010484869A CN111643513A CN 111643513 A CN111643513 A CN 111643513A CN 202010484869 A CN202010484869 A CN 202010484869A CN 111643513 A CN111643513 A CN 111643513A
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- cytarabine
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Abstract
The invention relates to a combination of aprepitant and cytarabine and an anti-leukemia effect thereof. In particular, the invention relates to methods of treating a blood cancer in a subject, alleviating symptoms of a blood cancer in a subject, or inhibiting proliferation of blood cancer cells, comprising administering to the subject aprepitant in combination with cytarabine. Further, the present invention relates to a medicament for treating leukemia, which comprises aprepitant and cytarabine, and optionally a pharmaceutically acceptable carrier.
Description
Technical Field
The invention relates to an anticancer effect of aprepitant and cytarabine. In particular to: methods of treating cancer, alleviating symptoms of cancer, or inhibiting proliferation of cancer cells in a subject by way of a combination; use of aprepitant in the preparation of a medicament or medicament for reducing the toxic side effects of cytarabine; and pharmaceutical products for the treatment of cancer.
Background
Cancer, one of the most prevalent diseases with morbidity and mortality worldwide, is rapidly growing worldwideMajor global public health problems[1]. Epidemiological statistics show that the leukemia accounts for 2.4 percent and 3.2 percent of the global cancer morbidity and mortality respectively and has a trend of rising year by year[2]. Acute Myeloid Leukemia (AML) is a malignant disease of the bone marrow characterized by clonal expansion and differentiation arrest of myeloid progenitor cells, and AML is the most common form of Acute leukemia in adults with a five-year survival rate of only 24%[3]。
The current standard therapeutic strategy for AML is still chemotherapy-centered, including remission-induction, consolidation and persistence, with the goal of induction therapy being complete remission and restoration of normal hematopoiesis[4]. General use of large doses of cytosine arabinoside and anthracyclines for induction therapy[4]However, the chemotherapy has great toxic and side effects, high recurrence rate and poor prognosis, and the survival rate is sharply reduced with the increase of age, and the five-year survival rate of patients of 65 years and above is only 7 percent[5]. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has long been considered the standard of therapy and the best opportunity to achieve a durable response, but is expensive and the difficulty in finding a matching donor remains a major problem. At present, the short-range problems of few chemotherapeutic drugs, poor targeting, high toxic and side effects and the like exist in AML clinical treatment, so that the search for new drugs and new targets with high efficiency and low toxicity is a problem which needs to be solved urgently in the AML clinical treatment at present.
NK-1R is a member of the G Protein-Coupled Receptor (GPCR) family[6]It is also a Tachykinin (tacchykinin) receptor involved in the regulation of a variety of physiological and pathophysiological pathways. NK-1R is present in the nervous system and peripheral tissues and is expressed in lymphocytes, monocytes, macrophages, NK cells and microglia[7]. NK-1R is also expressed in bone marrow cells and is considered to be a hematopoietic regulatory factor[8]. SP is an undecapeptide, a member of the tachykinin superfamily, having the highest affinity for NK-1R[9]. SP is involved in the regulation of many physiological and pathophysiological functions, such as pain, the cardiovascular system, via NK-1R signalsSystemic, affective and addictive disorders and cancer progression[10-13]. It has been found that NK-1R is present in glioblastoma[14]Breast cancer[15]Osteosarcoma[16]And colon cancer[17]Aprepitant, the first FDA-approved NK-1R antagonist, was used clinically to treat acute and delayed chemotherapy-induced nausea and vomiting (CINV)[18]The research shows that the traditional Chinese medicine composition has an obvious anti-tumor effect. The research shows that aprepitant serving as a high-selectivity NK1R antagonist can down-regulate the expression of cyclin D1, c-Myc and LEF-1 related proteins, and causes the cell cycle block of colon cancer cells at G2Phase and induce apoptosis[17]NK-1R antagonists are effective in inhibiting glioblastoma proliferation both in vitro and in vivo by dissociation of the β -arrestin complex, thereby inactivating the MAPK pathway[14]. Therefore, the NK-1R is used as a new molecular target for blocking tumor growth, and further development of effective NK-1R antagonists has important significance for treating cancers.
Cytarabine is a pyrimidine nucleoside analogue that can replace deoxycytidine into DNA, acting primarily in the S phase of DNA synthesis by cells. Can inhibit cell proliferation by preventing cell from entering S phase from G1 phase, and inhibiting DNA synthesis of cell[19]. The most commonly used induction chemotherapy regimen for AML patients involves 3 days of daunorubicin and 7 days of cytarabine, which can achieve a Complete Remission (CR) rate of 60-80% in young patients and 45-60% in elderly patients[20,21]. Although large doses of cytarabine have significant therapeutic effects, the toxic side effects are severe, including severe effects on both nervous system and organs[22]。
Disclosure of Invention
In order to provide a new treatment way or provide wider choices for patients with leukemia, the inventor of the invention finds that the combination of aprepitant and cytarabine has a remarkable anti-tumor effect, and the combination of cytarabine and aprepitant can remarkably reduce the toxic and side effects caused by the application of large dose of cytarabine, thereby providing more combined chemotherapy schemes for clinically treating patients with acute myeloid leukemia.
Accordingly, in one aspect the present invention provides a method of treating cancer in a subject comprising administering to said subject a therapeutically effective amount of aprepitant and cytarabine.
Another aspect of the invention provides the use of aprepitant and cytarabine in the preparation of a medicament or medicament for the treatment of cancer.
The invention also provides a medicament or a pharmaceutical composition comprising aprepitant and cytarabine.
In a third aspect, the present invention provides a method for reducing toxic side effects of cytarabine comprising the combined use of aprepitant and cytarabine.
The invention also provides application of aprepitant in preparing a medicament or medicament for reducing toxic and side effects of cytarabine.
Drawings
Fig. 1 shows the effect of cytarabine or aprepitant on cell proliferation activity of HL60 cells after 24 hours treatment alone, with significant differences in cytarabine or aprepitant itself on HL60 cell proliferation activity compared to 0 μ Μ group (/ P <0.01,/P < 0.001).
Fig. 2 shows the effect of aprepitant in combination with cytarabine on cell proliferation viability of HL60 cells after 24 hours, and the inhibition of HL60 cell viability was significantly different for the combination drug group compared to the drug group alone (P < 0.001).
FIG. 3 is a graph showing representative pictures of cells treated with HL60 by aprepitant in combination with cytarabine, wherein the scale indicates 50 μm.
Figure 4 is a graph of the effect of aprepitant in combination with cytarabine on HL60 cell cycle wherein: (A) after different medicine adding groups are treated for 24 hours, the cell cycle distribution condition of HL60 cells is detected by a flow cytometer; (B) and (3) carrying out proportion statistical analysis on cell cycle distribution under different dosing groups. Compared with a control group, the GO/G1 phase proportion of the drug-added group is obviously increased; the combined drug addition group showed a significant increase in the ratio of GO/G1 phases compared to the drug addition group alone (P <0.05, P < 0.001).
Fig. 5 is a graph of the effect of aprepitant in combination with cytarabine on apoptosis necrosis of HL60, wherein: (A) after different drug adding groups are treated for 24 hours, detecting Annexin V-FITC of HL60 cells and PI fluorescence distribution conditions by a flow cytometer; (B) and (5) counting the proportion of necrotic cells under different dosing groups. The proportion of necrosis was significantly increased in the combined drug-treated group compared to the drug-treated group alone (ns P > 0.05,. P <0.01,. P < 0.001).
Figure 6 is a graph of the effect of aprepitant in combination with cytarabine on PI uptake by HL60 cells, wherein: (A) the PI staining of different drug-added groups was photographed under a microscope. The scale in the figure represents 50 μm. (B) And (5) carrying out statistics on the proportion of PI dyeing of different medicine adding groups after the treatment of the different medicine adding groups for 24 hours and 48 hours. The cellular PI staining proportion of the combined drug-addition group was significantly increased compared to the drug-addition group alone (. about.p <0.01,. about.p < 0.001).
Figure 7 shows the effect of aprepitant in combination with cytarabine on LDH release from HL60 cells, with a significant increase in the relative release of LDH from the combined drug-treated groups at 24 hours (P <0.05, P < 0.001).
FIG. 8 shows the effect of aprepitant in combination with cytarabine on cell proliferation viability of HL60 cells after 24 hours of treatment after Nec-1 and Z-VAD-FMK pretreatment. Nec-1 and Z-VAD-FMK reversed the effect of inhibition of proliferation of HL60 cells after co-dosing compared to control without Nec-1 and Z-VAD-FMK pretreatment (. P <0.05,. P <0.01,. P < 0.001).
Figure 9 is a graph of the effect of aprepitant in combination with cytarabine on tumor growth in tumor bearing nude mice, wherein: (A) the tumor volume of the nude mice changed with time under different drug treatments, and the tumor volume of the combined drug group was significantly reduced compared with the cytarabine alone (ns P > 0.05, P < 0.01); (B) photographs of the transplanted tumor tumors taken from all mice on day 10; (C) the tumor weight of each group was significantly reduced compared to the control group and the combined group compared to the cytarabine alone (ns P > 0.05,. P <0.01) for each tumor excised from all mice on day 10.
Figure 10 is a graph of the effect of aprepitant in combination with cytarabine on body weight in nude tumor-bearing mice, wherein: (A) pictures of tumor-bearing nude mice treated with aprepitant in combination with cytarabine. (B) The weight of the nude mice changes with time under different drug treatments, and the weight of the mice treated by the drug does not change obviously.
FIG. 11 shows the effect of aprepitant in combination with cytarabine on the organ index of nude mice treated with tumor.
FIG. 12 shows the effect of aprepitant in combination with cytarabine on white blood cells, red blood cells, hemoglobin and platelets in nude mice treated with tumor bearing nude mice.
Detailed Description
The inventor of the invention has long-term and continuous researches and finds that the combined use of aprepitant and cytarabine has excellent antitumor effect.
Accordingly, in one aspect the present invention provides a method of treating cancer or alleviating the symptoms of cancer in a subject comprising administering to the subject an effective amount of a combination of aprepitant and cytarabine. The present invention also provides a method for inhibiting the proliferation of cancer cells (blood cancer cells) comprising the step of contacting said cancer cells with a combination of aprepitant and cytarabine. Yet another aspect of the present invention provides a pharmaceutical composition comprising aprepitant and cytarabine; and instructions for including the product in relation to the pharmaceutical composition.
For the subject of the present invention, it is preferably a mammal, more preferably a human. The present invention is illustrated by blood cancer cells, and the terms "cancer" or "cancer" herein are both blood cancers and their associated cancer cells, unless otherwise indicated or clearly contradicted by context.
For the pharmaceutical composition of the invention, it can be any aprepitant and the chemotherapeutic agent cytarabine that is capable of treating cancer or alleviating a symptom of cancer in a subject. As described in the above "background art", aprepitant is a highly selective NK1R antagonist and is clinically used for treating CINV, and it has been found that aprepitant has a broad-spectrum anti-tumor effect and inhibits the growth of cancer cells by targeted blocking of NK 1R. Cytarabine is the most common chemotherapeutic drug for acute myeloid leukemia. On the basis of the teaching of the invention, aprepitant can be combined with cytarabine to achieve the aim of the invention.
Aprepitant and cytarabine as active ingredients of the present invention may be used together with a pharmaceutically acceptable carrier. In addition to the active ingredients, the methods, uses and products of the invention may also comprise suitable agronomically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations.
For example, formulations suitable for injection or infusion include aqueous and non-aqueous sterile injection solutions, which may optionally contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
The active ingredients of the invention may optionally be combined with solid excipients and the resulting mixture optionally ground and, if desired, after addition of suitable auxiliaries, processed to give the desired dosage form. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose or starch preparations, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate, may be added.
Illustratively, the active ingredient of the invention may be used in a dosage of 1-15mg/kg of aprepitant and 1-10mg/kg of cytarabine, e.g. 2-12mg/kg of aprepitant and 2-8mg/kg of cytarabine. Preferably, aprepitant is 10mg/kg and cytarabine is 5 mg/kg.
According to the present invention, the pharmaceutical product (drug, medicament) or pharmaceutical composition of the present invention may be administered to a subject in any effective number of doses. Preferably, the pharmaceutical compositions of the present invention may be administered in multiple doses, for example from about 2 to about 15 doses, more preferably from about 4-10 doses, most preferably about 6 doses. In a particularly preferred embodiment, the pharmaceutical product (drug, medicament) or pharmaceutical composition of the invention is administered to the subject during the course of administration, e.g. injection, infusion or oral administration, at a frequency of about once every three weeks. In a particularly preferred embodiment, administration is by injection.
It will be appreciated that the pharmaceutical compositions of the invention may be formulated in any suitable manner for administration by any suitable route.
Dosage units of the pharmaceutical compositions of the invention are based on conventional administration to a subject. For example, a dosage unit may be administered more than once daily, once weekly, once monthly, etc. Dosage units may be administered on a twice/week basis, i.e., twice weekly, e.g., once every three days.
As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. The term "comprising" in any of the expressions herein, particularly in describing the method, use or product of the invention, is to be understood as including those products, methods and uses which consist essentially of and consist of the recited components or elements or steps. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
The instructions contained in the pharmaceutical product of the invention relating to the pharmaceutical product may contain the following: indications (e.g., blood cancer), dosages (e.g., as exemplified above), and possible side effects, among others.
The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
For a more clear illustration of the invention, reference is now made in detail to the following examples, which are intended to be purely exemplary of the invention and are not to be interpreted as limiting the application.
Examples
1. Materials and methods
1.1 materials, reagents and instruments
1.1.1 materials
Human acute myeloid leukemia cell HL60 was donated by the first Hospital affiliated with the medical college of Zhejiang university. Aprepitant and cytarabine are available from beijing solibao technologies ltd.
1.1.2 Primary reagents
1.1.3 reagent preparation
(1) Phosphate buffer (Phosphate buffer saline, PBS): accurately weighing 0.2g of potassium chloride, 8g of sodium chloride, 0.24g of potassium dihydrogen phosphate and 3.63g of disodium hydrogen phosphate dodecahydrate by using an electronic balance, adding a rotor cleaned by secondary water, dissolving a magnetic stirrer in the secondary water, adjusting the pH to 7.4, fixing the volume to 1000mL, subpackaging, sterilizing at high temperature and high pressure under the conditions of 121 ℃, 20 minutes and storing at 4 ℃.
(2) Aprepitant: 30mM stock solution was prepared in DMSO and stored at-20 ℃.
(3) Cytarabine: preparing 40mM stock solution with PBS, storing in a refrigerator at 80 deg.C, diluting the stock solution to 1mM working solution, storing in a refrigerator at 20 deg.C, taking out, and thawing at room temperature before use.
(4) MTT 250mg of MTT (Thiazolyl Blue tetrazolium Bromide) powder was accurately weighed by an electronic balance, dissolved in sterile PBS for internal use in a beaker, added with a rotor and wrapped with tinfoil paper in the dark, dissolved in the dark on a magnetic stirrer for 4-6 hours, and then the volume was adjusted to 50 mL. In a clean bench, the mixture was filtered through a sterilized 0.22. mu.M aqueous syringe filter, and the filtrate was dispensed into 1.5mL centrifuge tubes, wrapped with tinfoil, and stored at-20 ℃.
(5) PI: the powder was dissolved in sterile PBS to a stock solution of 10mg/mL and stored at-20 ℃. The stock solution was diluted to 1mg/mL with sterile PBS and stored at-20 ℃.
(6) Z-VAD-FMK: the powder was dissolved in sterile DMSO to 50mM stock and stored at-20 ℃.
(7) Neocriptin-1 (Nec-1): the powder was dissolved in sterile DMSO to 10mM stock and stored at-20 ℃.
(8) Cyclophosphamide: weighing a proper amount of cyclophosphamide into a 1.5mL centrifuge tube, adding a certain amount of sterile PBS solution, and uniformly blowing and oscillating by a gun to prepare the cyclophosphamide working solution with the concentration of 10 mg/mL.
1.1.4 Main Instrument
1.2 Experimental methods
1.2.1 cell culture
Observing the state and density of the cells by an inverted microscope every day, and when the cell density reaches 70-90%, carrying out passage according to the dilution ratio of 1:3 to 1: 6; sucking out cell culture solution, putting into a 15mL centrifuge tube, and centrifuging at 1000rpm for 5 min; removing supernatant, adding sterile PBS into the centrifuge tube to resuspend cells, centrifuging at 1000rpm for 5min, and washing twice; PBS is removed, a proper amount of fresh cell culture medium is added, and after uniform mixing, the mixture is transferred to a new cell culture dish according to a dilution ratio and cultured under normal culture conditions.
1.2.2 MTT assay
(1) The cells in the logarithmic growth phase were collected, counted using a Count star cell counter, and the cell density was adjusted to 1 × 104One strain per 100. mu.L was inoculated in a 96-well plate;
(2) after the plating is finished, 100 mu L of aprepitant is added, so that the final concentration of cytarabine is 0.4 mu m and 0.8 mu m, and the final concentration of aprepitant is 10 mu m, and a drug solvent treatment control group is arranged;
(3) the different inhibitors are added 1h in advance, wherein the final concentration of Nec-1 is 50 μ M, and the final concentration of Z-VAD-FMK is 10 μ M;
(4) after the specified time is reached, adding 10 mu L of MTT solution into each hole, and continuously incubating for 4 hours in a cell culture box;
(5) centrifuging at 1000rpm for 5min, removing supernatant, adding 150 μ L DMSO into each well, mixing, and further incubating in cell culture box for 30 min;
(6) measuring the light absorption values of A490 and A570 wavelengths by using a microplate reader, and deriving an Excel value;
(7) for the derived absorbance value, calculating according to the formula: cell proliferation activity (%) × (experimental OD-blank OD)/(control OD-blank OD) × 100%.
1.2.3 cell cycle assays
(1) Collecting cells in logarithmic growth phase, counting cells with a Count star cell counter, adjusting cell density to 1 × 106One/well was inoculated in 6-well plates;
(2) after the plate spreading is finished, adding two medicines to make the final concentration of cytarabine be 0.8 μm and the final concentration of aprepitant be 10 μm, and simultaneously setting a control group treated by medicine solvent;
(3) after the specified time is reached, collecting the cells in a 15mL centrifuge tube, centrifuging the cells at 1000rpm for 5min, washing the cell sediment with clean PBS solution for 2 times, and fixing the cell sediment with 75% alcohol overnight;
(4) the overnight fixed sample is centrifuged at 2000rpm for 10 min, washed with PBS solution for 2 times, 500 μ L of PI/RNase A staining working solution prepared according to the proportion of 9:1 is added into each tube of sample, after being blown and uniformly mixed, the tube is incubated for 30min in a room temperature and dark environment, and after the parameters are set by a flow cytometer, the tube is tested on a machine.
1.2.4 apoptosis and necrosis assays
(1) Collecting cells in logarithmic growth phase, counting cells with a Count star cell counter, adjusting cell density to 1 × 106One/well was inoculated in 6-well plates;
(2) after the plate spreading is finished, adding two medicines to make the final concentration of cytarabine be 0.8 μm and the final concentration of aprepitant be 10 μm, and simultaneously setting a control group treated by medicine solvent;
(3) after the specified time, the cells were collected in a 15mL centrifuge tube, centrifuged at 1000rpm for 5min, and the cell pellet was washed 2 times with clean PBS solution and centrifuged at 1000rpm for 5 min. Sucking out the supernatant PBS, adding 500 mu LBinding buffer in the apoptosis detection kit for resuspending cells, and removing the adhered cells by passing the cell suspension through a 200-mesh screen;
(4) and adding 5 mu L of Annexin V-FITC and 5 mu L of PI solution into each tube of sample, uniformly mixing by blowing, incubating for 20min in a room-temperature and dark environment, setting parameters by a flow cytometer, and detecting on a machine.
1.2.5 PI absorption experiment
(1) Collecting cells in logarithmic growth phase, counting cells with a Count star cell counter, adjusting cell density to 1 × 104One strain per 100. mu.L was inoculated in a 96-well plate; the drug concentration is 10 μm for aprepitant and 0.8 μm for Ara-c.
(2) After the specified time is reached, adding 10 mu L of PI working solution into each hole, and continuously incubating for 30min in a cell culture box;
(3) using an inverted fluorescence microscope to find a proper visual field, wherein 100-200 cells in the visual field are suitable;
(4) adjusting the focal length until the cell morphology is clear, firstly taking a white light picture, switching the same position into a green fluorescence picture, and exporting the picture after the shooting is finished;
(5) combining two photos of white light and red light under the same visual field into one photo by using Photoshop so as to observe clear PI absorbed cells; the total number of cells and the number of cells absorbing PI in each picture were counted using a Photoshop counting tool. Calculating according to a formula: PI absorption ratio (%) - (number of PI-absorbed cells)/(total number of cells) × 100%.
1.2.6 LDH Release detection assay
(1) Collecting cells in logarithmic growth phase, counting cells with a Count star cell counter, adjusting cell density to 2 × 104Per 100 mu LInoculating in a 96-well plate;
(2) then, the 96-well plate was placed in a cell incubator and cultured overnight by a conventional method, and the culture medium was aspirated and replaced with fresh culture medium containing 1% FBS. And sets the following groups: including cell-free culture fluid wells (background blank control wells), control cell wells without drug treatment (sample control wells), cell wells without drug treatment for subsequent lysis (sample maximum enzyme activity control wells), and drug-treated cell wells (drug-treated sample wells);
(3) for the drug-treated sample wells, the final concentration of aprepitant was 1 μm and the final concentration of cytarabine was 0.8 μm. Meanwhile, a drug solvent treated control group is set; for the sample maximum enzyme activity control hole, 1h before the preset detection time point, adding 20 mu L of LDH release reagent, repeatedly blowing and beating for a plurality of times, uniformly mixing, and then continuously incubating in a cell culture box;
(4) after the specified time had been reached, the 96-well plate was centrifuged at 400g for 5 min. Respectively taking 120 mu L of supernatant of each well, and adding the supernatant into a new 96-well plate;
(5) adding 60 μ L LDH detection working solution into each well, blowing, mixing, incubating in horizontal shaking table at room temperature in dark place for 30min
(6) Measuring light absorption values of A490 and A600 wavelengths by using a microplate reader, and deriving an Excel value;
(7) for the derived absorbance value, calculating according to the formula: LDH release (%) - (treated sample absorbance-blank well absorbance)/(absorbance of maximum enzyme activity of cells-blank well absorbance) × 100%.
1.2.7 experiment of nude mice tumorigenesis of HL60 cells by aprepitant and cytarabine
(1) Tumor formation in nude mice
Randomly dividing 16 nude mice with four-week age into 4 cages, adaptively culturing for two days, injecting 200 μ L10 mg/mL cyclophosphamide into abdominal cavity of each nude mouse every day after two days, continuously injecting for 2 days, collecting HL60 cells in logarithmic phase, washing with sterile PBS for three times, centrifuging at 1000rpm for 5 minutes, counting 20 μ L cell suspension before the last centrifugation, injecting 1 × 10 cells into each mouse7Each BALB/c nude mouse was injected with 200 cells subcutaneously on the back2L of cell suspension.
The nude mice were observed daily for back neoplasia and were padded and water every three days. When the tumor body of the nude mouse grows to 100-150mm3At the time, nude mice were randomly grouped.
(2) Administration treatment of nude mice
The nude mice are divided into four groups, namely a control group, an aprepitant group, an cytarabine group and a combined group, and then are numbered.
The administration is carried out once every two days, the administration amount of aprepitant is 10mg/kg, the administration amount of cytarabine is 5mg/kg, the control group is injected with PBS (phosphate buffer solution) into the abdominal cavity, the cytarabine group and the aprepitant group are respectively injected with 1002L cytarabine diluent and 1002L aprepitant diluent in situ, and the combination group is injected with 1002L cytarabine diluent and 100 mu L aprepitant diluent in situ. The tumor volume of the nude mice was recorded every two days while the body weight of the nude mice was weighed.
When the tumor volume of the nude mice exceeds 2000mm3The experiment was stopped and all nude mice were euthanized. The tumor body of the nude mouse was detached and the organ of the nude mouse was removed. The stripped tumor and viscera were weighed and counted. Meanwhile, whole blood of the nude mice is collected and subjected to routine blood analysis.
1.2.8 statistical analysis
At least three replicates of each experiment were performed and statistics are presented as Mean ± Mean standard error (Mean ± SEM). Statistical significance analysis was performed using SPSS according to data type. And (4) comparing whether the difference of the data is significant or not by using a t test, recording the significant difference P value in the detection result, and marking the P value into a statistical chart in a form of a dot. ns represents P > 0.05, P <0.01, P < 0.001.
2 results of the experiment
2.1 aprepitant enhances the sensitivity of HL60 cells to the cytotoxicity of cytarabine
The MTT experiment result shows that the cell proliferation activity of HL60 cells treated by cytarabine with the cell survival rate of 100 percent, 0.4 mu M, 0.8 mu M, 1.2 mu M, 1.6 mu M and 2.0 mu M of the control group for 24 hours is 89.17 +/-3.92 percent, 75.84 +/-2.93 percent, 74.16 +/-1.86 percent, 69.16 +/-2.38 percent and 62.18 +/-2.63 percent respectively. After 5 mu M, 10 mu M, 15 mu M, 20 mu M and 30 mu M aprepitant treatment of HL60 cells for 24h, the proliferation activity of the cells was 85.98 +/-2.53%, 71.07 +/-2.36%, 52.37 +/-0.95%, 50.47 +/-0.89% and 23.07 +/-1.58%, respectively (FIG. 1). And after treating HL60 cells with 10 mu M aprepitant and 0.4 mu M or 0.8 mu M cytarabine for 24 hours, the proliferation activities of the cells were 41.83 +/-3.96% 3 and 34.90 +/-1.87%, respectively, for HL60 cells, the sensitivity of the cells to cytarabine is 5.37 times that of 0.4 mu M cytarabine alone in combination with 0.4 mu M cytarabine, and 2.69 times that of 0.8 mu M cytarabine alone in combination with 0.8 mu M cytarabine (FIG. 2). HL60 cells were directly observed for cell status from an inverted microscope after being treated with 10. mu.M aprepitant and 0.4. mu.M or 0.8. mu.M cytarabine alone or in combination for 24 hours. The control group had normal cell morphology, good light transmission and high cell number, while the drug-added group had shriveled and crushed cells, increased cell debris and low cell number (FIG. 3).
Fig. 1, fig. 2 and fig. 3 visually demonstrate the effect of aprepitant in combination with cytarabine on the inhibition of HL60 cell proliferation.
2.2 aprepitant enhancement of cytarabine causes G0/G1 cycle arrest in HL60 cells
Cell cycle was measured using a cell cycle kit. After the drug treatment is carried out for 24 hours, both the aprepitant and the cytarabine can obviously block the cell cycle in the G0/G1 stage, and the cell cycle blocking effect of the combined group is more obvious. The statistical results showed that the control group had a G0/G1 phase ratio of 37.14. + -. 2.02%, the 0.8. mu.M cytarabine group had a G0/G1 phase ratio of 69.63. + -. 1.08%, the 10. mu.M aprepitant group had a G0/G1 phase ratio of 54.96. + -. 2.06%, and the combination group had a G0/G1 phase ratio of 76.02. + -. 1.51% (FIG. 4).
FIG. 4 visually demonstrates the effect of aprepitant to enhance cytarabine to induce cycle arrest in HL60 cells G0/G1.
2.3 Induction of HL60 cell necrosis by aprepitant and cytarabine
The apoptosis and necrosis of the cells are detected by Annexin V-FITC and PI double staining method. The Q4 quadrant is a normal cell group which is negative to both PI and Annexin V-FITC, the Q3 quadrant is an Annexin V-FITC positive and PI negative early apoptosis cell group, Q1 is a PI positive and Annexin V-FITC negative necrosis cell group, and Q2 is a PI and Annexin V-FITC positive late apoptosis cell group. After the aprepitant and the cytarabine are treated on HL60 cells for 24 hours, no obvious cell population in a Q3 region is observed, so that the results suggest that the aprepitant and the cytarabine inhibit the cell proliferation by increasing the proportion of HL60 necrotic cells.
The statistical results showed that the necrosis ratio of the control group was 5.33. + -. 0.24%, the cell necrosis ratio of the 0.8. mu.M cytarabine-treated group was 25.11. + -. 0.27%, the cell necrosis ratio of the 10. mu.M aprepitant-treated group was 11.83. + -. 0.30%, and the cell necrosis ratio of the combination group-treated group was 36.35. + -. 1.27% (FIG. 5). The combination of aprepitant and cytarabine can induce necrosis of HL60 cells, and compared with a single medicine-added group, the combination of aprepitant and cytarabine can obviously increase the necrosis ratio of HL60 cells.
Figure 5 visually demonstrates that aprepitant enhances cytarabine-induced necrosis of HL60 cells.
2.4 Effect of aprepitant in combination with cytarabine on PI uptake by HL60 cells
For necrotic cells, PI can enter the cell membrane and show red fluorescence under a fluorescence microscope because the integrity of the cell membrane is lost, and further can be used for judging the damage degree of the cell membrane. After the aprepitant and cytarabine are combined to treat HL60 cells for 24 hours and 48 hours, the cell morphology is changed, part of the cells are obviously broken, and the number of PI stained cells is increased. PI staining statistical analysis, after 24 hours of drug treatment, the PI staining rate of the 0.8 μ M cytarabine-alone treatment group was 11.06 + -1.90%, while the PI staining rate of the aprepitant combined with cytarabine was 27.45 + -0.88%. After 48 hours of drug treatment, the PI staining rate of the 0.8 μ M cytarabine-alone treated group was 35.59. + -. 2.57%, while the PI staining rate of aprepitant combined with cytarabine was 51.79. + -. 3.03% (FIG. 6).
Fig. 6 visually shows that aprepitant and cytarabine can significantly increase the PI staining rate, which indicates that treatment with aprepitant and cytarabine can significantly increase the damage degree of the cell membrane of HL60 cell.
2.5 aprepitant combined with cytarabine to promote LDH release
The damage of the cell membrane structure caused by the necrosis of the cells can cause the enzyme in the cytoplasm to be released into the culture solution, wherein the enzyme comprises Lactate Dehydrogenase (LDH) with relatively stable enzyme activity, and the LDH content is detected by a lactate dehydrogenase cytotoxicity detection kit. LDH release was statistically analyzed, and based on the relative release amount of 1 in the control group, the relative release amount of 7.32. + -. 0.09% in the 0.8. mu.M cytarabine-alone treated group and 10.54. + -. 0.58% in the aprepitant plus cytarabine combination after 24 hours of drug treatment (FIG. 7). Further shows that the treatment of aprepitant and cytarabine can obviously increase the damage degree of HL60 cell membranes.
Figure 7 shows intuitively that the LDH release of the combined drug-addition set is significantly higher than that of the sole drug-addition sets of aprepitant and cytarabine. The combination of aprepitant and cytarabine increases the damage degree of HL60 cell membranes.
2.6 Nec-1 and Z-VAD-FMK reverse the inhibition of cell proliferation by aprepitant in combination with cytarabine
Nec-1 is a necrosis inhibitor, Z-VAD-FMK is a specific Caspase inhibitor, and Nec-1 and Z-VAD-FMK are further added into an MTT cell proliferation activity test for pretreatment, and whether cell necrosis caused by the combination of Ara-C and Aprepitant can be relieved to a certain extent or not is observed. The statistical results showed that the cell proliferation activity in the Nec-1 pretreated group was 40.26 ± 2.15%, the cell proliferation activity in the Z-VAD-FMK treated group was 38.06 ± 3.34%, the cell proliferation activity in the combined two inhibitors pretreated group was 57.72 ± 2.02%, and the cell proliferation activity in the combined non-inhibitor treated group was 28.97 ± 2.41% (fig. 8), thus further demonstrating that aprepitant is combined with cytarabine to inhibit cell proliferation by increasing the proportion of HL60 necrotic cells.
FIG. 8 is a schematic representation showing that Nec-1 and Z-VAD-FMK reverse inhibition of cell proliferation by aprepitant in combination with cytarabine
2.7 Activity of aprepitant to enhance the growth of Heterotransplanted tumors of cytarabine in tumor-bearing nude mice
To further verify that aprepitant combined with cytarabine inhibited proliferation of HL60 cells, we constructed a model of a humanized mouse graft tumor of HL60 cells. Solid tumors are formed by subcutaneous injection of HL60 cells, after treatment of different drug treatment groups, the tumor growth of nude mice of a control group is the most rapid, the tumor volume is the largest, the tumor volume growth of an aprepitant treatment group and an cytarabine treatment group is slower than that of the control group, the tumor volume growth of a combined group is the slowest, and the tumor volume is the smallest. Data analysis was performed on day 10 tumor volumes, 2175.0. + -. 341.9mm for the control group3While the tumor volume of the combination group was reduced to 828.4 + -232.4 mm3. The tumor volume of the cytarabine group is 1869.0 +/-153.5 mm3There was no significant difference compared to the control group (fig. 9). Data analysis of tumor weights at day 10 revealed that the tumor weights of the control group were 1.05 + -0.11 g, the tumor weights of the cytarabine group were 0.89 + -0.11 g, the tumor weights of the aprepitant group were 0.50 + -0.14 g, and the tumor weights of the combination group were 0.34 + -0.10 g, with significant differences between the combination group and the cytarabine-alone treated group (fig. 9).
There was no significant difference in body weight gain between groups (figure 10). Statistical analysis of the organ indices revealed no significant difference in the organ indices between individuals and groups (fig. 11). Blood routine analysis is carried out on the collected whole blood of the mice, and statistical results show that the number of white blood cells, the number of red blood cells, the number of hemoglobin and the number of platelets among all groups have no significant difference (figure 12), which indicates that the aprepitant and the cytarabine have no obvious toxic or side effect on the nude mice.
Figure 9 shows intuitively that aprepitant in combination with cytarabine can significantly inhibit mouse tumor growth in animal experiments. Fig. 10, fig. 11 and fig. 12 visually show that the aprepitant and cytarabine have no obvious toxic or side effect on mice in animal experiments.
In conclusion, aprepitant combined with cytarabine has the effect of increasing the toxicity of cytarabine on HL60 cells in vivo and in vitro. In a cell experiment, aprepitant and cytarabine can obviously inhibit the proliferation of HL60 cells and induce the necrosis of HL60 cells, and the aprepitant and cytarabine can destroy HL60 cell membranes, so that the PI absorption and the LDH release are obviously increased. In animal experiments, aprepitant and cytarabine can obviously inhibit the growth of transplanted tumors when used for treating nude mice, and meanwhile, the aprepitant and cytarabine have no obvious toxic or side effect.
It will be appreciated by those of ordinary skill in the art that methods, starting materials, and the like, other than those specifically exemplified can be employed in the practice of the present invention without undue experimentation. All art-known functional equivalents of any such methods and starting materials, and the like, are intended to be encompassed by the present invention. It will also be understood by those skilled in the art that various changes and modifications may be made to the invention as described in the specification and claims, and that the invention includes all such changes and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any 2 or more of said steps or features.
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Claims (10)
1. use of aprepitant in combination with cytarabine in the manufacture of a medicament for treating a cancer, alleviating a symptom of a cancer in a subject, or inhibiting proliferation of a cancer cell, wherein the cancer is a blood cancer or a blood cell cancer.
2. The use of claim 1, wherein the cancer is a primary cancer or a secondary cancer.
3. The use according to claim 2, wherein the cancer is acute leukemia.
4. The use of claim 1, wherein said cancer cells are acute leukemia cancer cells.
5. The use of claim 1, wherein the subject is a mammal.
6. The use of claim 5, wherein said mammal is a human.
7. A pharmaceutical composition or kit for the treatment of cancer comprising aprepitant and cytarabine.
8. The pharmaceutical composition or kit of claim 7, wherein the cancer is leukemia.
9. Use of aprepitant in the preparation of a medicament or medicament for reducing the toxic side effects of cytarabine.
10. The use of claim 9, wherein the drug or medicament is a drug or medicament for the treatment of a blood cancer.
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| CN113209107A (en) * | 2021-04-02 | 2021-08-06 | 浙江理工大学 | Application of aprepitant and chemotherapeutic drug combination in preparation of drug for treating acute lymphocytic leukemia |
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| CN113116902A (en) * | 2021-04-02 | 2021-07-16 | 浙江理工大学 | Application of antiemetic aprepitant in preparation of medicine for treating acute lymphocytic leukemia |
| CN113209107A (en) * | 2021-04-02 | 2021-08-06 | 浙江理工大学 | Application of aprepitant and chemotherapeutic drug combination in preparation of drug for treating acute lymphocytic leukemia |
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