肿瘤多药耐药机制及化学逆转剂研究进展
Research Progress of Multidrug Resistance Mechanism and Reverser in Tumor

作者: 郭牡丹 , 胥秀英 , 徐豆豆 , 刘晶晶 , 郑一敏 :重庆理工大学药学与生物工程学院,重庆; Andrease Melzer :英国邓迪大学,英国 邓迪;

关键词: 肿瘤多药耐药机制化学逆转剂Tumor Multidrug Resistance Mechanism Chemical Reversal Agent

摘要: 肿瘤多药耐药(Multidrug Resistance, MDR)系肿瘤细胞对结构与作用靶位不同的抗肿瘤药物产生交叉耐药性的现象,MDR是肿瘤化疗失败的主要原因。本文对肿瘤MDR发生机制及肿瘤MDR化学逆转剂进展进行了综述。

Abstract: Multidrug resistance (MDR) is a phenomenon in which tumor cells produce cross-resistance to antitumor drugs with different structures and target targets. MDR is the main reason for the failure of tumor chemotherapy. This article reviews the mechanism of tumor MDR and the progress of tumor MDR chemical reversal agents.

1. 引言

肿瘤严重威胁人类生命和健康 [1] [2] [3],目前90%以上肿瘤患者治疗失败都与肿瘤MDR有关 [3]。本文对肿瘤MDR发生机制以及逆转肿瘤MDR的进展进行了综述。

2. 多药耐药机制

肿瘤细胞MDR形成机制是多因素参与的复杂过程,ABC转运蛋白家族、miRNA、肿瘤干细胞(cancer stem cell, CSC)、自噬诱导、诱导异常、DNA损伤修复、药物靶点突变及表观遗传诱导与之有关(图1)。

Figure 1. Potential mechanism of tumor MDR [4]

图1. 肿瘤MDR潜在机制 [4]

2.1. ABC转运蛋白家族

ABC转运蛋白能外排细胞内药物,分ABCA到ABCG亚家族 [5],共49种不同类型的转运蛋白 [6]。如ABCB1促使癌细胞对米托蒽醌,沙奎那韦,表鬼臼毒素和蒽环类药物的耐药性 [7] [8] [9] [10]。ABCG2与乳腺癌、结肠癌、胃癌、小细胞肺癌和卵巢癌MDR关系密切 [11]。ABC转运蛋白已经成为开发新型逆转剂的靶点 [12]。

2.2. miRNA调控

miRNA是一类小非编码RNA,它通过调节ABC转运蛋白,凋亡蛋白,DNA损伤修复,自噬和药物代谢酶等(图2)产生肿瘤MDR [13] [14]。

Figure 2. miRNA regulates MDR pathway in tumor cells [15]

图2. miRNA调控肿瘤细胞MDR路径 [15]

2.3. 肿瘤干细胞(CSC)调控

CSC具有自我更新和分化特性,多处于细胞G0期,具有很高的端粒酶活性及DNA复制修复能力,是造成肿瘤耐药的最根本原因 [16]。通过高表达ABC转运蛋白和抗凋亡基因而逃避化疗及放疗,导致肿瘤复发和转移 [17]。

2.4. 自噬诱导

自噬是一个高度保守的细胞降解和循环过程 [18]。自噬通过降解药物分子发挥其细胞保护作用,帮助癌细胞逃避凋亡 [19]。

2.5. 凋亡异常

肿瘤细胞通过抑制细胞凋亡而引起MDR [20]。肿瘤细胞凋亡异常有凋亡蛋白抑制因子、Caspase-8蛋白、死亡受体等表达异常 [21]。

2.6. DNA损伤和修复(DDR)

肿瘤细胞DNA修复可以切除抗肿瘤药物致命性的DNA损伤,降低基于破坏肿瘤细胞DNA药物的效果。最新研究表明,在10,489例肿瘤内,80个核心DDR基因中有13个被显著扩增和过表达,带有DDR基因扩增的肿瘤可产生化疗耐药而导致整体生存率下降 [22]。

2.7. 表观遗传诱导

表观遗传是指细胞内除遗传信息以外的其他可遗传物质的改变,与肿瘤MDR的恶性表型密切 [23]。

3. 化学逆转剂

3.1. 临床研究中逆转肿瘤MDR药物

3.1.1. 靶向ABCB1耐药逆转剂

靶向ABCB1/p-gp/MDR1耐药逆转剂(图3)经历了三代发展(表1),目前已经研发至第四代。由于毒副作用大,至今没有应用于临床。

Table 1. Targeted ABCB1 resistance reversal agents

表1. 靶向ABCB1耐药逆转剂

维拉帕米 Verapamil 环孢素A Cyclosporin A 右旋维拉帕米 dexverapamil >哌啶类衍生物(VX-710) VX-710 环孢素A的同系 PSC83 物 环丙基二苯并环庚烷类物质 3 Zosuquidar (LY335979) 环丙基二苯并环庚烷类物质 剂 Laniquidar (R101933) 新型氨基哌啶类逆转 S9788

Figure 3. Targeting ABCB1 resistance reversal agent

图3. 靶向ABCB1耐药逆转剂

3.1.2 谷胱甘肽转移酶(GST)/谷胱甘肽(GSH)抑制剂

GST/GSH过度表达而产生MDR [29]。抑制GSH的药物有丁硫氨酸亚碘胺(BSO)、依地尼酸(EA)、硝基咪哇类等。BSO是谷氨酰半胱氨酸合成酶的特异性抑制剂,它通过降低细胞内GSH的浓度,增加肿瘤细胞对抗癌药物的敏感性逆转MDR。EA可以抑制GST的活性,在GST的催化作用下,EA与GSH结合形成的EA-GSH复合物比EA更强作用 [29] [30]。小分子化合物APR-246 (图4)具有调节细胞内GSH水平的作用,毒副作用小,是潜在的MDR逆转剂,正在进行临床试验 [31]。

3.1.3. 拓扑异构酶(Topo)抑制剂

Topo是细胞凋亡过程中关键的核内酶。临床用药初期,TopoI抑制剂(伊立替康、拓扑替康等)抗肿瘤敏感性较高,但易产生耐药性。TopoII抑制剂XR11576 (图5)可逆转TopoI/ABCB1/MRP导致的MDR [32],目前在I期临床研究中。TopoI和TopoII抑制剂联合使用可产生一加一大于二的协同作用,达到逆转MDR的效果,国内外已进入临床实验 [33] [34] [35]。

Figure 4. APR-246 structural formula

图4. APR-246结构式

Figure 5. XR11576

图5. XR11576

3.1.4. 酪氨酸激酶抑制剂(TKIs)

TKIs (图6)抑制ABC转运蛋白活性,逆转肿瘤细胞对一些传统化疗药物的MDR。如伊马替尼(Imatinib)可逆转ABCB1过度表达的表皮癌细胞系(KB-G2)对长春新碱、紫杉醇、依托泊苷的耐药性 [29] [36],尼洛替尼(Nilotinib)逆转ABCC1介导的肿瘤多药耐药,但会改变传统抗癌药物的血药动力学,不宜用于临床。厄洛替尼联合曲妥珠单抗表现出较好的耐受性和增强抗肿瘤活性,联合化疗治疗MDR患者值得进一步临床研究 [37]。

达沙替尼(Dasatinib)属第二代酪氨酸激酶抑制剂,用于已经治疗,包括甲磺酸伊马替耐药或不能耐受的慢性骨髓性白血病所有病期的成人患者,不良反应大部分轻度到中度 [38]。

奥西替尼(Oxitinib)是第三代不可逆的口服EGFR-TKI,可以有效和选择性地抑制EGFR敏感突变和EGFR T790M耐药突变,MET扩增是EGFR-TKI产生MDR原因之一,临床前研究和初步临床资料表明,联合使用MET抑制剂和EGFR-TKI是治疗EGFR-TKIs获得性耐药的有效方法 [39]。

3.1.5. 其它

蛋白激酶C(PKC)可以改变药物在MDR细胞中的蓄积,部分MDR肿瘤细胞中PKC活性增加。

尼洛替尼 Nilotinib 伊马替尼 Imatinib 奥西替尼 Oxitinib 达沙替尼Dasatinib

Figure 6. TKIs inhibitors

图6. TKIs抑制剂

CGP41251 (图7)是高度选择性的PKC抑制剂,具有抗肿瘤及有效逆转MDR的作用,使MDR细胞对阿霉素和长春新碱的敏感性增加。然而,由于它逆转MDR的同时也产生较大的毒性作用,限制了临床应用 [40]。GS-4997 (图7)是一种凋亡信号调节激酶1 (ASK1)抑制剂,处于III期临床试验中,研究发现GS-4997可以抑制肿瘤MDR细胞中ABCB1和ABCG2的表达,提示GS-4997有希望发展MDR逆转剂 [41]。

CGP41251 GS-4997

Figure 7. CGP41251 and GS-4997

图7. CGP41251和GS-4997

3.2. 逆转肿瘤MDR临床前研究药物

论当前逆转肿瘤MDR临床前研究药物结构见图8,进展见表2

Table 2. Drugs that reverse tumor MDR preclinical research

表2. 逆转肿瘤MDR临床前研究药物

NFV FTC Ko143 A-770041 PHA-665752 NVP-TAE684 Venetoclax

Figure 8. The drugs that reverse tumor MDR preclinical research

图8. 逆转肿瘤MDR临床前研究药物

3.3. 逆转肿瘤MDR先导化合物

3.3.1. 天然先导化合物

以查耳酮、7-异戊烯氧基香豆素(7-IP)和麻疯树二萜类天然产物为先导合成的化合物(图9)具有良好的MDR逆转效果(表3)。

Table 3. Lead compounds derived from natural products

表3. 来源于天然产物的先导化合物

1 2 1e 19 25 26

Figure 9. Compounds synthesized using natural products as the lead

图9. 以天然产物为先导合成的化合物

3.3.2. 合成先导化合物

近年来化学合成的LS-2-3j、479、C4、D3和D6先导化合物结构见图10,进展见表4

Table 4. Lead compound from chemical synthesis

表4. 来源于化学合成的先导化合物

LS-2-3j 479 C4 D3 D6

Figure 10. The lead compound of chemical synthesis

图10. 化学合成的先导化合物

4. 结语与展望

肿瘤MDR是肿瘤治疗失败主要原因,明确MDR机制,联合用药是克服肿瘤MDR的有效手段。目前化学逆转剂毒副作用限制了临床应用,开发高效低毒的靶向药物是当务之急,先导化合物的发现与结构优化是主要努力方向之一,有望开发理想的MDR逆转剂。

基金项目

国家高端外国专家项目(GDW20155200280)。

NOTES

*通讯作者。

文章引用: 郭牡丹 , 胥秀英 , 徐豆豆 , 刘晶晶 , Andrease Melzer , 郑一敏 (2020) 肿瘤多药耐药机制及化学逆转剂研究进展。 有机化学研究, 8, 1-13. doi: 10.12677/JOCR.2020.81001

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