Fighting metallodrug resistance through alteration of drug metabolism and blockage of autophagic flux by mitochondria-targeting AIEgens.
Fighting metallodrug resistance through alteration of drug metabolism and blockage of autophagic flux by mitochondria-targeting AIEgens.
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通过改变药物代谢和靶向线粒体的 AIEgens 阻断自噬流来对抗金属药物耐药性
DOI：
10.1039/d1sc06722b
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发表时间：
2022-02-02
期刊：
影响因子：
8.4
通讯作者：
Su Z
中科院分区：
文献类型：
--
作者：
Su Y;Lin H;Tu Y;Wang MM;Zhang GD;Yang J;Liu HK;Su Z
金属药物耐药性在癌症治疗中引起了极大的关注。根据顺铂（cis-Pt）的抗癌机制，提出了通过线粒体功能障碍克服顺铂耐药的新策略。首次合成了两个靶向于肺癌细胞的聚集诱导荧光团（AIEgens），命名为DP-PPh 3和TPE-PPh 3，它们通过改变药物代谢（上调内流CTR 1和下调外流MRP 2）和阻断自噬流（不能降解自噬体）来克服肺癌细胞（A549 R）的顺式铂耐药性，显示出上级能力。这项研究是AIEgens首次用于治疗顺式铂耐药癌细胞。此外，其分子机制也得到了充分的揭示。三苯基膦修饰的AIEgens DP-PPh 3和TPE-PPh 3不仅成功实现了A549 R细胞线粒体的聚集和成像，而且激活了对A549 R细胞的细胞毒作用。DP-PPh 3和TPE-PPh 3可诱导ROS产生，破坏线粒体结构，损害线粒体和糖酵解代谢。此外，这些药物的抗癌功效在体外A549 R细胞的3D多细胞肿瘤球体（MCTS）和体内荷瘤裸鼠中得到证实。这种AIE-PPh 3策略不仅促进了对癌细胞的细胞毒性，而且为金属药物耐药性的治疗提供了新的途径。
Metallodrug resistance has attracted a great deal of attention in cancer treatment. According to the cisplatin (cis-Pt) anticancer mechanism, a new strategy to overcome cis-Pt resistance through mitochondrial dysfunction is proposed. Two mitochondria-targeted aggregation-induced emission fluorogens (AIEgens) were first synthesized, named DP-PPh3 and TPE-PPh3, which showed superior capacities to overcome the cis-Pt resistance of lung cancer cells (A549R) by the alteration of drug metabolism (up-regulation of influx CTR1 and down-regulation of efflux MRP2) and blockage of autophagic flux (failure of the degradation of autophagosomes). This study is the first time that AIEgens are utilized in the treatment of cis-Pt resistant cancer cells. Moreover, the underlying molecular mechanism was fully revealed. Triphenylphosphonium (PPh3)-decorated AIEgens DP-PPh3 and TPE-PPh3 not only successfully realized aggregation and the imaging of mitochondria in A549R cells, but also activated cytotoxicity towards A549R cells. DP-PPh3 and TPE-PPh3 could induce ROS production, disrupt the mitochondrial structure, and impair mitochondrial and glycolytic metabolism. Furthermore, the anticancer efficacy of these drugs was demonstrated in 3D multicellular tumor spheroids (MCTSs) of A549R cells in vitro and in tumor-bearing nude mice in vivo. This AIE-PPh3 strategy not only promoted cytotoxicity towards cancer cells but also provided a new pathway for the treatment of metallodrug resistance.
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影响因子：
21.8
作者：
Busschaert N;Park SH;Baek KH;Choi YP;Park J;Howe ENW;Hiscock JR;Karagiannidis LE;Marques I;Félix V;Namkung W;Sessler JL;Gale PA;Shin I
通讯作者：
Shin I
影响因子：
4.4
作者：
Indo, Hiroko P.;Davidson, Mercy;Majima, Hideyuki J.
通讯作者：
Majima, Hideyuki J.
吗啡诱导脊髓神经元中 PINK1/Parkin 介导的线粒体自噬功能障碍，这意味着参与抗伤害耐受
影响因子：
5.5
作者：
Kong, Hong;Jiang, Chun-Yi;Liu, Wen-Tao
通讯作者：
Liu, Wen-Tao
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1083/jcb.201402104
发表时间：
2014-04-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kane LA;Lazarou M;Fogel AI;Li Y;Yamano K;Sarraf SA;Banerjee S;Youle RJ
通讯作者：
Youle RJ