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Fighting metallodrug resistance through alteration of drug metabolism and blockage of autophagic flux by mitochondria-targeting AIEgens

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...

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Detalles Bibliográficos
Autores principales: Su, Yan, Lin, Hai, Tu, Ying, Wang, Meng-Meng, Zhang, Guan-Dong, Yang, Jin, Liu, Hong-Ke, Su, Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809423/
https://www.ncbi.nlm.nih.gov/pubmed/35222927
http://dx.doi.org/10.1039/d1sc06722b
Descripción
Sumario: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-PPh(3) and TPE-PPh(3), 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 (PPh(3))-decorated AIEgens DP-PPh(3) and TPE-PPh(3) not only successfully realized aggregation and the imaging of mitochondria in A549R cells, but also activated cytotoxicity towards A549R cells. DP-PPh(3) and TPE-PPh(3) 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-PPh(3) strategy not only promoted cytotoxicity towards cancer cells but also provided a new pathway for the treatment of metallodrug resistance.