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 (AIEgens) were first synthesized, named DP-PPh and TPE-PPh, 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).

Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid.

Alpha lipoic acid (LA) is a natural compound and coenzyme with sufficient safety information for serving as a promising anticancer agent. To further clarify the mechanism of action (MoA), two Ir(iii) complexes with the functionalized α-lipoic acid (NN-LA, NN, 2,2-bipyridine derivative), namely Ir1 and Ir2, were synthesized, where Ir1 possessed a half-sandwich structure with the formula [Ir(Cp*)(NN-LA)Cl]PF (Cp* = 1,2,3,4,5-pentamethyl-cyclopentadiene) and Ir2 possessed the cyclometalated structure with the formula [Ir(CN)(NN-LA)]PF (CN = 2-phenylpyridine). Even though both complexes were constructed based on the same NN-LA ligand, Ir1 showed no cytotoxicity (IC > 200 μM), which was due to its low lipophilicity for hard penetration into the cancer cells, easy hydrolysis, and reaction with GSH.