WO2018072269A1 - 非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用 - Google Patents

非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用 Download PDF

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WO2018072269A1
WO2018072269A1 PCT/CN2016/108725 CN2016108725W WO2018072269A1 WO 2018072269 A1 WO2018072269 A1 WO 2018072269A1 CN 2016108725 W CN2016108725 W CN 2016108725W WO 2018072269 A1 WO2018072269 A1 WO 2018072269A1
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tumor
steroidal anti
tyrosine kinase
inflammatory drug
drug
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张辉
张译文
潘婷
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Sun Yat Sen University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

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  • the present invention relates to a novel field of use of known compounds, and in particular to the use of non-steroidal anti-inflammatory drugs for increasing the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • Axl kinase inhibitors may be used in early cancer patients, especially those who are prone to cancer metastasis, in order to maximize the efficacy of Axl kinase inhibitors.
  • Axl kinase inhibitor used to treat a drug is generally a secondary mutation of a targeted kinase or a compensatory upregulation of other receptor tyrosine kinases.
  • Overexpression of Axl kinase is thought to be an important cause of drug resistance produced by compensatory upregulation.
  • a targeted drug develops resistance, it can be combined with an Axl kinase inhibitor to produce a synergistic effect.
  • tumor cells can also develop drug resistance through epithelial mesenchymal transition mechanisms.
  • overexpression of Axl kinase induces tumor cell resistance to traditional chemotherapeutic drugs such as anti-mitotic drugs through epithelial-mesenchymal transition.
  • Axl inhibitors can be used in combination with first-line drugs to slow down the patient's drug resistance, thereby achieving the effect of inhibiting cancer progression.
  • Axl kinase has attracted extensive attention from drug developers as a novel cancer therapeutic target.
  • Axl kinase small molecule inhibitors have become a research hotspot.
  • the development of kinase inhibitors against the Axl target is still in its early stages relative to many receptor tyrosine kinase inhibitors, and relatively few studies have been conducted.
  • Effective and rapid Axl target inhibitors have become a hot spot for drug discovery.
  • Non-steroidal anti-inflammatory drugs are a class of drugs that have antipyretic and analgesic effects, and most have anti-inflammatory and anti-rheumatic effects. For some rheumatic diseases, such as early rheumatoid arthritis, senile arthritis and Early ankylosing spondylitis is the drug of choice.
  • Non-steroidal anti-inflammatory drugs not disclosed in the prior art can also be used to increase the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • the present invention provides a use of a non-steroidal anti-inflammatory drug for increasing the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • non-steroidal anti-inflammatory drugs in the preparation of drugs for degrading Axl.
  • non-steroidal anti-inflammatory drug for the preparation of a medicament for enhancing the sensitivity of a tumor cell to a tyrosine kinase inhibitor is aspirin, acetaminophen or ibuprofen.
  • the expression level of Axl is increased.
  • non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen and acetaminophen can induce receptor Axl degradation and affect Axl protein. Tumor resistance, metastasis, and recurrence are induced, thereby increasing the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • a medicament for enhancing the sensitivity of tumor cells to tyrosine kinase inhibitors comprising a non-steroidal anti-inflammatory drug, said non-steroidal anti-inflammatory drug being aspirin, acetaminophen or ibuprofen.
  • An antitumor drug comprising a non-steroidal anti-inflammatory drug and a tyrosine kinase inhibitor, the non-steroidal anti-inflammatory drug being aspirin, acetaminophen or ibuprofen.
  • the drug can reduce the transition of epithelial cells to stromal cells and inhibit tumor metastasis.
  • the drug can reduce the formation of cancer stem cells and alleviate tumor recurrence.
  • the present invention has the following beneficial effects:
  • the present invention employs a non-steroidal anti-inflammatory drug in combination with a tyrosine kinase inhibitor to enhance the sensitivity of the tumor to tyrosine kinase inhibitors.
  • a non-steroidal anti-inflammatory drug in combination with a tyrosine kinase inhibitor to enhance the sensitivity of the tumor to tyrosine kinase inhibitors.
  • the present invention employs a non-steroidal anti-inflammatory drug in combination with a tyrosine kinase inhibitor to inhibit tumor metastasis.
  • a non-steroidal anti-inflammatory drug in combination with a tyrosine kinase inhibitor to inhibit tumor metastasis.
  • the use of non-steroidal anti-inflammatory drugs can significantly reduce the expression of marker proteins during the transition of epithelial cells to stromal cells, significantly inhibiting the mouse model in vivo. The formation of lung metastases.
  • the invention adopts a combination of a non-steroidal anti-inflammatory drug and a tyrosine kinase inhibitor, inhibits the formation of tumor stem cells after use of the targeted drug, reduces the expression of the tumor stem cell-specific protein, and inhibits the tumor after the targeted drug treatment.
  • a non-steroidal anti-inflammatory drug and a tyrosine kinase inhibitor
  • Non-steroidal anti-inflammatory drugs the safety of the human body has long been tested in clinical practice, avoiding a long cycle of new drug development.
  • the invention has the advantages of low cost, high safety, and the like, and provides good technical support for the extensive development of anti-tumor treatment. It provides a strong practical basis for us to further improve the treatment of cancer, and has important development value and promotion significance.
  • Figure 1 shows the effect of non-steroidal anti-inflammatory drugs on the degradation of Axl in different tumor cells.
  • Figure 2 shows that non-steroidal anti-inflammatory drugs enhance the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • Figure 3 shows the effect of a combination of non-steroidal anti-inflammatory drug aspirin and trimetinib on tumor metastasis.
  • Figure 4 shows that the combination of non-steroidal anti-inflammatory drug aspirin and trimetinib inhibits tumor stem cell formation and inhibits tumor recurrence after targeted drug administration.
  • the value of 12 on the abscissa is used as the standard.
  • the lower curves represent Vehicle, Asp, Tra, and Tra+Asp; the columns in the right histogram in Figure c represent Vehicle, Asp, Tra, and Tra+Asp from left to right.
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used are, if not specified, commercially available reagents and materials.
  • non-steroidal anti-inflammatory drugs aspirin, acetaminophen or ibuprofen degrade Axl in different tumor cell lines and enhance the sensitivity of tumor cells to tyrosine kinase inhibitors.
  • the tumor cell line is plated into a 6-well plate.
  • aspirin Asp
  • acetaminophen Ace
  • ibuprofen Ibu
  • the tumor cell line is plated into a 96-well plate.
  • aspirin Aspirin
  • Acetaminophen Ace
  • ibuprofen Ibu
  • the tyrosine kinase inhibitors Trametatin Tra
  • Dalafinil Dab
  • Sorafenib Sor
  • Erlotinib Erl
  • the present invention verifies that aspirin, acetaminophen, ibuprofen can degrade Axl in lung cancer, liver cancer, colorectal cancer, breast cancer, melanoma cell lines in an in vitro cell line experiment (see Fig. 1). ).
  • the killing effect on tumor cells was significantly increased after combination with tyrosine kinase inhibitors (see Figure 2).
  • the 1 ⁇ 10 6 melanoma cell line A375 was subcutaneously injected into the lateral abdomen of NOD-SCID mice. After tumor formation, the mice were administered with trimetinib (1 mg/kg body weight) and aspirin (20 mg/kg body weight). ), administered every other day.
  • mice were melanoma cell line B16-F10, 5 ⁇ 10 5 cells were injected from the tail vein into C57 mice, and the mice were administered with trimetinib (1 mg / Kg body weight), aspirin (20 mg/kg body weight), administered every other day. On the 14th day of administration, the lungs of the mice were taken, photographed, and the nodules of lung metastasis were counted.
  • the non-steroidal anti-inflammatory drug aspirin aspirin
  • trimetatin trimetatin
  • mice The 1 ⁇ 10 6 melanoma cell line A375 was subcutaneously injected into the lateral abdomen of NOD-SCID mice. After tumor formation, the mice were administered with trimetinib (1 mg/kg body weight) and aspirin Aspirin (20 mg). /kg body weight), administered every other day. Mice administered to 14 days were withdrawn and the tumor volume continued to be measured.

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Abstract

非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用，所述非甾体类抗炎药为阿司匹林、布洛芬或对乙酰氨基酚，其能够降解Axl激酶，从而提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性。

Description

非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用 技术领域
本发明涉及已知化合物的新用途领域，具体地，涉及非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用。
背景技术
在癌症治疗过程中，肿瘤转移及耐药性是影响抗癌药物疗效的两大难点，也是导致癌症死亡率居高不下的主要原因。Axl表达上调与肿瘤转移的病理机制密切相关。诸多研究结果显示，抑制Axl激酶的活性可以有效的阻滞肿瘤细胞的生长、迁移和侵袭。因此，Axl激酶抑制剂有可能用于早期癌症患者，尤其是那些容易出现癌细胞转移的患者中，从而最大程度的发挥Axl激酶抑制剂的疗效。
使用受体酪氨酸激酶抑制剂治疗患者时造成耐药的机制一般为靶向激酶的二次突变或其他受体酪氨酸激酶的代偿性上调。Axl激酶的超表达被认为是代偿性上调所产生耐药性的一个重要原因。当一个靶向药物出现耐药性之后将其同Axl激酶抑制剂联合使用会产生药效的协同效果。除此之外，肿瘤细胞也可以通过上皮细胞间充质转化机制产生耐药性。在这个过程中，Axl激酶的超表达通过上皮细胞-间充质转化使肿瘤细胞产生对传统化疗药物如抗有丝分裂药物的耐药性。在这种情况下，Axl抑制剂可以通过和一线药物联用的方式来减缓患者的耐药性，从而达到抑制癌症进展的效果。
近年来，Axl激酶作为新颖的癌症治疗靶点已经引起药物研发人员的广泛重视，Axl激酶小分子抑制剂已经成为研究热点。相对于许多受体酪氨酸激酶抑制剂来说，针对Axl靶点的激酶抑制剂的开发还处于早期阶段，研究也相对较少。有效，且快速的Axl靶点抑制剂成为了药物研发的热点。
非甾体类抗炎药(NSAIDs)是一类具有解热、镇痛，多数还有抗炎、抗风湿作用的药物，对于一些风湿性疾病，如早期类风湿关节炎、老年性关节炎及早期强直性脊柱炎等是首选药物。现有技术中未公开非甾体类抗炎药还可以用于提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性。
发明内容
本发明为了克服现有技术的上述缺陷，提供非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用。
为了实现上述目的，本发明是通过以下技术方案予以实现的：
非甾体抗炎药在制备降解Axl药物中的应用。
非甾体抗炎药在制备增强肿瘤细胞对酪氨酸激酶抑制剂敏感性的药物中的应用，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。使用络氨酸激酶抑制剂的肿瘤细胞，Axl表达量会升高，本发明发现阿司匹林，布洛芬，对乙酰氨基酚等非甾体类抗炎药能够诱导受体Axl降解，影响Axl蛋白介导的肿瘤耐药，转移，复发，从而提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性。
非甾体抗炎药和酪氨酸激酶抑制剂联合用药在制备抗肿瘤药物中的应用，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
一种增强肿瘤细胞对酪氨酸激酶抑制剂敏感性的药物，含有非甾体抗炎药，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
一种抗肿瘤药物，含有非甾体抗炎药和酪氨酸激酶抑制剂，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
该药物可以减少上皮细胞向间质细胞的转变，抑制肿瘤转移。
该药物可以减少肿瘤干细胞的形成，缓解肿瘤复发。
与现有技术相比，本发明具有如下有益效果：
本发明采用非甾体抗炎药与酪氨酸激酶抑制剂联用，增强肿瘤对酪氨酸激酶抑制剂的敏感性。经体内体外的实验证实，在使用酪氨酸激酶抑制剂治疗肿瘤时，配合使用非甾体抗炎药，可以得到更强的肿瘤杀伤效果。
本发明采用非甾体抗炎药与酪氨酸激酶抑制剂联用，抑制肿瘤的转移。在使用酪氨酸激酶抑制剂治疗肿瘤时，配合使用非甾体抗炎药，可以显著的降低上皮细胞向间质细胞的转变过程中标志性蛋白质的表达，在小鼠体内模型中，显著抑制了肺部转移灶的形成。
本发明采用非甾体抗炎药与酪氨酸激酶抑制剂联用，抑制了靶向药使用后肿瘤干细胞的形成，降低了肿瘤干细胞特异性蛋白的表达，并且抑制了靶向药治疗后肿瘤的复发。
非甾体抗炎药，对人体的安全性早已经过临床实践的检验，避免了新药研发漫长的周期。该发明具有成本低廉、安全性高等优点，为抗肿瘤治疗的广泛开展提供了良好的技术支持。为我们进一步提高肿瘤治疗提供了强有力的实践基础，具有重要的开发价值和推广意义。
附图说明
图1为非甾体类抗炎药在不同肿瘤细胞中降解Axl的效果。
图2为非甾体类抗炎药增强肿瘤细胞对酪氨酸激酶抑制剂的敏感性。
图3为非甾体类抗炎药阿司匹林与曲美替尼联合使用抑制肿瘤转移的效果。
图4为非甾体类抗炎药阿司匹林与曲美替尼联合使用抑制肿瘤干细胞形成，并抑制肿瘤靶向用药后的复发，图a中，以横坐标的12的数值为标准，从上往下的曲线分别代表Vehicle、Asp、Tra、Tra+Asp；图c中右边的柱状图中的柱子，从左往右分别代表Vehicle、Asp、Tra、Tra+Asp。
具体实施方式
下面结合说明书附图和具体实施例对本发明作出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1
非甾体类抗炎药阿司匹林、对乙酰氨基酚或布洛芬在不同肿瘤细胞系中对Axl的降解作用，以及增强肿瘤细胞对酪氨酸激酶抑制剂敏感性。
(1)将肿瘤细胞系铺板至6孔板中，待细胞融合率达到30～40％时，在细胞培养基中分别加入阿司匹林(Asp)，对乙酰氨基酚(Ace)，布洛芬(Ibu)，浓度为200μM，培养48小时之后，对Axl的蛋白表达量进行检测。
(2)将肿瘤细胞系铺板至96孔板中，待细胞融合率达到30～40％时，在细胞培养基中加入阿司匹林(Asp)，对乙酰氨基酚(Ace)，布洛芬(Ibu)，浓度为200μM，同时加入酪氨酸激酶抑制剂曲美替尼(Tra)，达拉菲尼(Dab)，索拉非尼(Sor)和厄洛替尼(Erl)。培养48小时之后，使用CCK8技术，对肿瘤细胞的活性进行检测。
由上述实验的结果可知，本发明在体外细胞系实验中验证阿司匹林，对乙酰氨基酚，布洛芬可以在肺癌，肝癌，结直肠癌，乳腺癌，黑色素瘤细胞系中降解Axl(见图1)。同时，在和酪氨酸激酶抑制剂联用之后，对肿瘤细胞的杀伤作用显著提高(见图2)。
实施例2
以黑色素瘤为例，非甾体类抗炎药阿司匹林(Asp)，联合使用曲美替尼(Tra)抑制肿瘤转移。
(1)将1×106黑色素瘤细胞系A375皮下注射到NOD-SCID小鼠侧腹部，成瘤之后，小鼠体内给药曲美替尼(1mg/kg体重)，阿司匹林(20mg/kg体重)，隔天给药。
(2)给药至14天的小鼠，取肿瘤细胞，消化成为单细胞悬液。对其中上皮细胞向 间质细胞的转变过程中标志性蛋白质进行检测。
(3)构建小鼠肿瘤肺转移模型，使用小鼠的黑色素瘤细胞系B16-F10，5×105细胞从尾静脉注射至C57小鼠体内，小鼠体内给药曲美替尼(1mg/kg体重)，阿司匹林(20mg/kg体重)，隔天给药。给药第14天取小鼠肺部，拍照，对肺转移的小结进行计数。
由上述实验的结果可知，阿司匹林和曲美替尼联合用药，可以显著抑制上皮细胞向间质细胞的转变过程中标志性蛋白质的表达。并且在肿瘤肺转移的模型中，显著地降低肺转移(见图3)。
实施例3
以黑色素瘤为例，非甾体类抗炎药阿司匹林(Asp)，联合使用曲美替尼(Tra)抑制肿瘤干细胞形成，并抑制肿瘤靶向用药后的复发。
(1)将1×106黑色素瘤细胞系A375皮下注射到NOD-SCID小鼠侧腹部，成瘤之后，小鼠体内给药曲美替尼Trametinb(1mg/kg body weight),阿司匹林Aspirin(20mg/kg body weight)，隔天给药。给药至14天的小鼠，撤药，并继续测量肿瘤体积。
(2)给药至14天的小鼠，取肿瘤组织，切片，使用免疫组化技术鉴定干细胞蛋白的表达。并将肿瘤组织消化成为单细胞悬液，使用流式细胞技术检测干细胞蛋白的表达。
由上述实验的结果可知，阿司匹林和曲美替尼联合用药，可以显著抑制肿瘤靶向用药后的复发，并抑制肿瘤干细胞的形成(见图4)。

Claims (8)

  1. 非甾体抗炎药在制备降解Axl药物中的应用。
  2. 非甾体抗炎药在制备增强肿瘤细胞对酪氨酸激酶抑制剂敏感性的药物中的应用，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
  3. 非甾体抗炎药和酪氨酸激酶抑制剂联合用药在制备抗肿瘤药物中的应用，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
  4. 一种抗肿瘤药物，其特征在于，含有非甾体抗炎药和酪氨酸激酶抑制剂，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
  5. 一种增强肿瘤细胞对酪氨酸激酶抑制剂敏感性的药物，其特征在于，含有非甾体抗炎药，所述的非甾体抗炎药为阿司匹林、对乙酰氨基酚或布洛芬。
  6. 根据权利要求4所述的药物，其特征在于，该药物可以减少上皮细胞向间质细胞的转变，抑制肿瘤转移。
  7. 根据权利要求4所述的药物，其特征在于，该药物可以减少肿瘤干细胞的形成，缓解肿瘤复发。
  8. 根据权利要求4所述的药物，其特征在于，所述非甾体类抗炎药诱导受体Axl降解，影响Axl蛋白介导的肿瘤耐药，转移，复发。
PCT/CN2016/108725 2016-10-21 2016-12-06 非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用 Ceased WO2018072269A1 (zh)

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