WO2023040716A1 - Use of nicotinamide adenine dinucleotide in treatment of doxorubicin-induced cardiotoxicity - Google Patents
Use of nicotinamide adenine dinucleotide in treatment of doxorubicin-induced cardiotoxicity Download PDFInfo
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 87
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- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 title claims abstract description 14
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Definitions
- the invention relates to the application of nicotinamide adenine dinucleotide in treating cardiotoxicity induced by doxorubicin, and belongs to the technical field of biomedicine.
- Doxorubicin is one of the most widely used anti-tumor drugs in clinical practice, and its main mechanism is to kill tumor cells by inhibiting DNA and RNA synthesis.
- cardiotoxicity caused by doxorubicin often limits its clinical application.
- great progress has been made in reducing cardiotoxicity by encapsulating doxorubicin in liposomes, it is still impossible to completely prevent myocardial injury caused by doxorubicin. Therefore, it is urgent to discover new targets for the treatment of cardiotoxicity caused by doxorubicin from a new perspective.
- doxorubicin Abnormal myocardial energy metabolism is an important pathological basis of doxorubicin-induced myocardial injury, and mitochondria, as the main place to provide ATP, play a key role in it. It has been reported that doxorubicin can lead to increased apoptosis of the mitochondrial pathway in cardiomyocytes, dysregulation of mitophagy homeostasis, and metabolic dysfunction such as the tricarboxylic acid cycle. Therefore, improving mitochondrial function could serve as a potential target to prevent doxorubicin-induced myocardial injury.
- Nicotinamide adenine dinucleotide is an essential coenzyme to maintain mitochondrial metabolism and function.
- NAD+ can act as an electron acceptor to transfer energy in different metabolic pathways such as fatty acid oxidation and tricarboxylic acid cycle.
- NAD+ is also required for mitochondrial oxidative phosphorylation, and NAD+ deficiency will result in the inability of mitochondria to produce ATP.
- the therapeutic advantage of targeting NAD+ against doxorubicin-induced cardiotoxicity has not yet been explored.
- the technical problem to be solved by the present invention is: how to improve the cardiotoxicity induced by doxorubicin.
- the present invention provides the application of nicotinamide adenine dinucleotide in the preparation of drugs for treating doxorubicin-induced cardiotoxicity.
- the medicament includes a medically acceptable carrier and an effective amount of an active ingredient, and the active ingredient is nicotinamide adenine dinucleotide.
- the present invention proves that the heart function of the DOX+NAD group is significantly improved compared with the DOX+Control group through animal experiments; the present invention proves that the proportion of dead cells in the DOX+NAD group is significantly lower than that of the DOX+PBS group through cell experiments;
- the present invention proposes the application of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity for the first time.
- the use of NAD can reduce the death of cardiomyocytes caused by doxorubicin and relieve the cardiotoxicity caused by doxorubicin.
- To combat the side effects of doxorubicin expand the scope of use of doxorubicin, and improve the prognosis of tumor patients who are clinically treated with doxorubicin.
- Fig. 1 is the left ventricular ejection fraction (LVEF) result of detection mouse model
- Fig. 2 is the left ventricular fractional contraction rate (LVFS) result of detecting mouse model
- Fig. 3 is the death and life staining result of cardiomyocytes; Wherein, green represents living cells (shown by dots in the figure), red represents dead cells (shown by circles in the figure);
- Figure 4 is the proportion of dead cells in each group
- N means not significant (no statistical difference); *: means p ⁇ 0.05; **: means p ⁇ 0.01; ***: means p ⁇ 0.001.
- the DOX+Control group and the DOX+NAD group were intraperitoneally injected with DOX (15mg/kg, Sigma, D1515), and then the Sham+NAD group and the DOX+NAD group continued to NAD (50mg/kg/d, Selleck, S2518) was injected intraperitoneally, and the same amount of normal saline was injected into the Sham+Control group and DOX+Control group, and the cardiac function of the mice was checked 7 days later.
- Echocardiography was detected at 4 weeks, and the frequency of the probe was 30 MHz. Specifically, after isoflurane gas anesthesia, the M-mode images were recorded when the heart rate of the mouse was maintained at 450-500 beats/min. B-Mode images of parasternal long-axis view and apical four-chamber view were collected. The parasternal left ventricular short axis was taken, and 2D ultrasound was used to show the left ventricular short axis view. M-mode ultrasound was used to record the left ventricular motion at the papillary muscle level. Functional indicators include: left ventricular ejection fraction (LVEF), left ventricular fractional contraction rate (LVFS).
- LVEF left ventricular ejection fraction
- LVFS left ventricular fractional contraction rate
- Cardiomyocyte life-and-death staining SPF-grade male C57BL/6 mice (purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.), aged 8-10 weeks, weighing 20-25g, were used to extract primary cardiomyocytes from adult mice , divided into 4 groups (PBS group; NAD group; DOX+PBS group; DOX+NAD group), the intervention conditions are as follows: DOX+NAD group (DOX 1uM+NAD 500uM), DOX+PBS group (DOX 1uM+equivalent PBS) , NAD group (NAD 500uM), PBS group (equal amount of PBS), after 24 hours of intervention, use Calcein/PI Cell Viability and Cytotoxicity Detection Kit (beyotime, C2015S) to stain the cells for life and death, and you can see dead cells after DOX intervention The proportion increased significantly (P ⁇ 0.001), the proportion of dead cells in the DOX+NAD group was less than that in the DOX+PBS group (P ⁇
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Abstract
Disclosed is the use of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity, which belongs to the technical field of biomedicines. It has been proved by experiments on animals in the present invention that the cardiac function of the DOX + NAD group is significantly improved as compared with the DOX + Control group. It has been proved by cell experiments in the present invention that the proportion of death cells of the DOX + NAD group is significantly reduced as compared with the DOX + PBS group. According to the present invention, the use of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity is proposed for the first time, the death of myocardial cells caused by doxorubicin can be reduced by means of using NAD, the cardiotoxicity caused by same is relieved, the side effects caused by the use of the same can be resisted, the application range thereof is expanded, and the prognosis of tumor patients using same is clinically improved.
Description
本发明涉及烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用，属于生物医药技术领域。The invention relates to the application of nicotinamide adenine dinucleotide in treating cardiotoxicity induced by doxorubicin, and belongs to the technical field of biomedicine.
阿霉素(doxorubicin，DOX)是目前临床使用最为广泛的抗肿瘤药物之一，其主要机制是通过抑制DNA以及RNA合成，从而达到杀死肿瘤细胞的效果。然而，阿霉素导致的心脏毒性常常限制其临床应用。虽然目前通过脂质体包裹阿霉素等减轻其心脏毒性的技术已经取得了很大的进展，但仍旧无法完全预防阿霉素导致的心肌损伤。因此，亟需从新的视角去发现阿霉素导致的心脏毒性治疗的新靶点。Doxorubicin (DOX) is one of the most widely used anti-tumor drugs in clinical practice, and its main mechanism is to kill tumor cells by inhibiting DNA and RNA synthesis. However, cardiotoxicity caused by doxorubicin often limits its clinical application. Although great progress has been made in reducing cardiotoxicity by encapsulating doxorubicin in liposomes, it is still impossible to completely prevent myocardial injury caused by doxorubicin. Therefore, it is urgent to discover new targets for the treatment of cardiotoxicity caused by doxorubicin from a new perspective.
心肌能量代谢异常是阿霉素诱导的心肌损伤的重要病理基础，线粒体作为提供ATP的主要场所，在其中发挥着关键作用。有报道显示，阿霉素可以导致心肌细胞线粒体途径的凋亡增加，线粒体自噬稳态失调，三羧酸循环等代谢功能紊乱。因此改善线粒体功能，可以作为防止阿霉素诱导的心肌损伤的潜在靶点。Abnormal myocardial energy metabolism is an important pathological basis of doxorubicin-induced myocardial injury, and mitochondria, as the main place to provide ATP, play a key role in it. It has been reported that doxorubicin can lead to increased apoptosis of the mitochondrial pathway in cardiomyocytes, dysregulation of mitophagy homeostasis, and metabolic dysfunction such as the tricarboxylic acid cycle. Therefore, improving mitochondrial function could serve as a potential target to prevent doxorubicin-induced myocardial injury.
烟酰胺腺嘌呤二核苷酸(NAD+)是维持线粒体代谢与功能所必须的辅酶。首先，NAD+可以作为电子受体，在脂肪酸氧化以及三羧酸循环等不同代谢途径中传递能量。其次，NAD+也是线粒体氧化磷酸化所必需的，NAD+缺乏将导致线粒体无法产生ATP。有研究显示，线粒体功能的异常通常伴随着NAD+的减少。而补充NAD+可以显著改善线粒体功能。目前，已有一些通过补充NAD+前体，提高NAD+水平以治疗代谢性疾病的临床研究展开。但是目前针对NAD+对阿霉素诱导的心脏毒性的治疗优势还没有被发掘。Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme to maintain mitochondrial metabolism and function. First, NAD+ can act as an electron acceptor to transfer energy in different metabolic pathways such as fatty acid oxidation and tricarboxylic acid cycle. Second, NAD+ is also required for mitochondrial oxidative phosphorylation, and NAD+ deficiency will result in the inability of mitochondria to produce ATP. Studies have shown that abnormalities in mitochondrial function are usually accompanied by a reduction in NAD+. Supplementing with NAD+ can significantly improve mitochondrial function. At present, there have been some clinical studies on the treatment of metabolic diseases by supplementing NAD+ precursors and increasing NAD+ levels. However, the therapeutic advantage of targeting NAD+ against doxorubicin-induced cardiotoxicity has not yet been explored.
发明内容Contents of the invention
本发明所要解决的技术问题是：如何改善阿霉素诱导的心脏毒性。The technical problem to be solved by the present invention is: how to improve the cardiotoxicity induced by doxorubicin.
为了解决上述技术问题，本发明提供了烟酰胺腺嘌呤二核苷酸在制备治疗阿霉素诱导的心脏毒性的药物中的应用。In order to solve the above technical problems, the present invention provides the application of nicotinamide adenine dinucleotide in the preparation of drugs for treating doxorubicin-induced cardiotoxicity.
优选地，所述药物包括医学上可接受的载体和有效量的活性成分，所述活性成分为烟酰胺腺嘌呤二核苷酸。Preferably, the medicament includes a medically acceptable carrier and an effective amount of an active ingredient, and the active ingredient is nicotinamide adenine dinucleotide.
与现有技术相比，本发明的有益效果在于：Compared with prior art, the beneficial effect of the present invention is:
1.本发明通过动物实验，证明DOX+NAD组比DOX+Control组心功能有明显改善；本发明通过细胞实验，证明DOX+NAD组相比DOX+PBS组死亡细胞比例明显降低；1. The present invention proves that the heart function of the DOX+NAD group is significantly improved compared with the DOX+Control group through animal experiments; the present invention proves that the proportion of dead cells in the DOX+NAD group is significantly lower than that of the DOX+PBS group through cell experiments;
2.本发明首次提出烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用，采用NAD可以减少阿霉素引起的心肌细胞死亡，缓解阿霉素导致的心脏毒性，可以对抗阿霉素使用产生的副作用，扩大阿霉素的使用范围，改善临床上使用阿霉素的肿瘤患者的预后。2. The present invention proposes the application of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity for the first time. The use of NAD can reduce the death of cardiomyocytes caused by doxorubicin and relieve the cardiotoxicity caused by doxorubicin. To combat the side effects of doxorubicin, expand the scope of use of doxorubicin, and improve the prognosis of tumor patients who are clinically treated with doxorubicin.
图1为检测小鼠模型的左室射血分数(LVEF)结果；Fig. 1 is the left ventricular ejection fraction (LVEF) result of detection mouse model;
图2为检测小鼠模型的左室短轴收缩率(LVFS)结果；Fig. 2 is the left ventricular fractional contraction rate (LVFS) result of detecting mouse model;
图3为心肌细胞死活染色结果；其中，绿色代表活细胞(图中用点示出)，红色代表死细胞(图中用圈示出)；Fig. 3 is the death and life staining result of cardiomyocytes; Wherein, green represents living cells (shown by dots in the figure), red represents dead cells (shown by circles in the figure);
图4为各组别死亡细胞比例；Figure 4 is the proportion of dead cells in each group;
其中，图中“NS”：表示not significant(没有统计学差异)；*：表示p＜0.05；**：表示p＜0.01；***：表示p＜0.001。Among them, "NS" in the figure: means not significant (no statistical difference); *: means p<0.05; **: means p<0.01; ***: means p<0.001.
为使本发明更明显易懂，兹以优选实施例，并配合附图作详细说明如下。In order to make the present invention more comprehensible, preferred embodiments are described in detail below with accompanying drawings.
实施例Example
本实施例通过动物体内实验验证了烟酰胺腺嘌呤二核苷酸在治疗阿霉素诱导的心脏毒性中的应用：This example verified the application of nicotinamide adenine dinucleotide in the treatment of doxorubicin-induced cardiotoxicity through animal experiments:
1)实验动物分组及动物模型制备：选用SPF级雄性C57BL/6小鼠(购自上海杰思捷实验动物有限公司)，周龄为8-10周，体重20-25g，分为四组(Sham+Control组；Sham+NAD组；DOX+Control组；DOX+NAD组)，Sham+NAD组以及DOX+NAD组连续7天腹腔注射NAD(50mg/kg/d，Selleck，S2518)， Sham+Control组以及DOX+Control组注射等量生理盐水，第8天DOX+Control组，DOX+NAD组腹腔注射DOX(15mg/kg，Sigma，D1515)，随后Sham+NAD组以及DOX+NAD组继续每天腹腔注射NAD(50mg/kg/d，Selleck，S2518)，Sham+Control组以及DOX+Control组注射等量生理盐水，7天后查看小鼠心功能。1) Experimental animal grouping and animal model preparation: SPF grade male C57BL/6 mice (purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.), aged 8-10 weeks, weighing 20-25g, were selected and divided into four groups ( Sham+Control group; Sham+NAD group; DOX+Control group; DOX+NAD group), Sham+NAD group and DOX+NAD group were intraperitoneally injected with NAD (50 mg/kg/d, Selleck, S2518) for 7 consecutive days, Sham+ The Control group and the DOX+Control group were injected with the same amount of normal saline. On the 8th day, the DOX+Control group and the DOX+NAD group were intraperitoneally injected with DOX (15mg/kg, Sigma, D1515), and then the Sham+NAD group and the DOX+NAD group continued to NAD (50mg/kg/d, Selleck, S2518) was injected intraperitoneally, and the same amount of normal saline was injected into the Sham+Control group and DOX+Control group, and the cardiac function of the mice was checked 7 days later.
2)超声心动图评价小鼠心功能：于4周检测超声心动图，探头频率为30MHz。具体为异氟烷气麻动物后，当小鼠的心率保持在450-500次/分钟时记录M-mode图像。采集胸骨旁长轴切面、心尖四腔切面B-Mode图像。取胸骨旁左室短轴，2D超声示左室短轴切面，在乳头肌水平应用M型超声记录左心室运动情况。功能学指标包括：左室射血分数(LVEF)、左室短轴收缩率(LVFS)。比较各组小鼠心脏形态及功能变化。所有测量值均为连续5个心动周期的平均值，由3名经验丰富的技术人员进行。结果显示：DOX组小鼠心功能指标明显低于Sham组，DOX组注射烟酰胺腺嘌呤二核苷酸后小鼠心功能改善，DOX+NAD组小鼠比DOX+Control组小鼠EF％高10.24％(P＜0.05)；DOX+NAD组小鼠比DOX+Control组小鼠FS％高8.987％(P＜0.05)；Sham组注射NAD后小鼠与生理盐水对照组小鼠相比，EF及FS无差异，如图1、2所示。2) Echocardiography to evaluate the heart function of mice: Echocardiography was detected at 4 weeks, and the frequency of the probe was 30 MHz. Specifically, after isoflurane gas anesthesia, the M-mode images were recorded when the heart rate of the mouse was maintained at 450-500 beats/min. B-Mode images of parasternal long-axis view and apical four-chamber view were collected. The parasternal left ventricular short axis was taken, and 2D ultrasound was used to show the left ventricular short axis view. M-mode ultrasound was used to record the left ventricular motion at the papillary muscle level. Functional indicators include: left ventricular ejection fraction (LVEF), left ventricular fractional contraction rate (LVFS). The changes in heart shape and function of mice in each group were compared. All measurements are the average of 5 consecutive cardiac cycles, performed by 3 experienced technicians. The results showed that the cardiac function index of the mice in the DOX group was significantly lower than that in the Sham group, the cardiac function of the mice in the DOX group was improved after injection of nicotinamide adenine dinucleotide, and the EF% of the mice in the DOX+NAD group was higher than that of the mice in the DOX+Control group 10.24% (P<0.05); FS% of mice in DOX+NAD group was 8.987% higher than that in DOX+Control group (P<0.05); EF and FS no difference, as shown in Figures 1 and 2.
3)心肌细胞死活染色：选用SPF级雄性C57BL/6小鼠(购自上海杰思捷实验动物有限公司)，周龄为8-10周，体重20-25g，提取成年小鼠原代心肌细胞，分为4组(PBS组；NAD组；DOX+PBS组；DOX+NAD组)，干预条件如下：DOX+NAD组(DOX 1uM+NAD 500uM)，DOX+PBS组(DOX 1uM+等量PBS)，NAD组(NAD 500uM)，PBS组(等量PBS)，干预24小时候使用Calcein/PI细胞活性与细胞毒性检测试剂盒(beyotime，C2015S)对细胞进行死活染色，可以看到DOX干预后死细胞比例显著上升(P＜0.001)，DOX+NAD组死细胞比例少于DOX+PBS组(P＜0.001)，PBS组与NAD组相比死亡细胞比例无差异，如图3、4所示。3) Cardiomyocyte life-and-death staining: SPF-grade male C57BL/6 mice (purchased from Shanghai Jiesijie Experimental Animal Co., Ltd.), aged 8-10 weeks, weighing 20-25g, were used to extract primary cardiomyocytes from adult mice , divided into 4 groups (PBS group; NAD group; DOX+PBS group; DOX+NAD group), the intervention conditions are as follows: DOX+NAD group (DOX 1uM+NAD 500uM), DOX+PBS group (DOX 1uM+equivalent PBS) , NAD group (NAD 500uM), PBS group (equal amount of PBS), after 24 hours of intervention, use Calcein/PI Cell Viability and Cytotoxicity Detection Kit (beyotime, C2015S) to stain the cells for life and death, and you can see dead cells after DOX intervention The proportion increased significantly (P<0.001), the proportion of dead cells in the DOX+NAD group was less than that in the DOX+PBS group (P<0.001), and there was no difference in the proportion of dead cells between the PBS group and the NAD group, as shown in Figures 3 and 4.
上述实施例仅为本发明的优选实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。The foregoing embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any form and in essence. It should be pointed out that those of ordinary skill in the art can also make Several improvements and supplements should also be considered as the protection scope of the present invention.
Claims (2)
- 烟酰胺腺嘌呤二核苷酸在制备治疗阿霉素诱导的心脏毒性的药物中的应用。Application of nicotinamide adenine dinucleotide in preparation of medicine for treating doxorubicin-induced cardiotoxicity.
- 如权利要求1所述的应用，其特征在于，所述药物包括医学上可接受的载体和有效量的活性成分，所述活性成分为烟酰胺腺嘌呤二核苷酸。The application according to claim 1, characterized in that the drug comprises a medically acceptable carrier and an effective amount of an active ingredient, and the active ingredient is nicotinamide adenine dinucleotide.
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