Antitumor properties and mechanisms of mitochondria-targeted Ag(i) and Au(i) complexes containing N-heterocyclic carbenes derived from cyclophanes

Abstract

Metal/N-heterocyclic carbene (NHC) complexes hold great opportunities for the development of novel antitumor metallodrugs. Herein, four Ag(I) and Au(I) complexes containing NHCs derived from cyclophanes have been prepared and characterized as potential anticancer agents. These complexes show higher cytotoxicity than cisplatin against several cancer cell lines including a cisplatin-resistant cell line. The Au(I) complexes display higher anticancer activity than the corresponding Ag(I) complexes. Moreover, all the complexes are less cytotoxic than cisplatin on the normal human liver cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the mitochondria, especially for the Au(I) complexes. Interestingly, although both Ag(I) and Au(I) complexes can influence mitochondrial integrity, they induce cancer cell death through different mechanisms. The Ag(I) complexes mainly induce caspase- and reactive oxygen species (ROS)-independent early apoptosis. However, Au(I) complexes induce both early apoptosis and late apoptosis through caspase- and ROS-dependent pathways. These studies may open up an avenue for a better understanding of the impact of metal centers on antitumor potentialities and mechanisms.

Phosphorescent iridium(III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agents

“…The impact of the tested compounds on MMP was determined as previously described [21]. Briefly, HeLa cells were treated with the tested compounds at the indicated concentrations for 6 h. The cells were then collected and stained with JC-1 (5 mg/mL) and analyzed immediately by flow cytometry (FACSCalibur™, Becton Dickinson, NJ, USA).…”

“…Cell growth inhibitory effects of the tested compounds were determined by MTT assay as previously described [21]. The impact of the tested compounds on MMP was determined as previously described [21].…”

“…Western blotting was performed as previously described [21]. Briefly, HeLa cells seeded in 6 cm culture dishes were exposed to 3 at 1 mM, 5 mM or 10 mM for 12 h. Cells were lysed in radio-immunoprecipitation assay (RIPA) buffer.…”

“…The impact of 1e3 on ROS levels was determined as previously described [21]. Briefly, cells were treated with Ir(III) for 6 h and then incubated with H 2 DCFDA …”

“…The exploration of metaleNHCs as potential anticancer drugs constitutes a very rapidly growing field of research [16e19]. Cancer cells are characterized by abnormally high mitochondrial membrane permeabilization, and it has been shown that metaleNHCs can achieve some degree of selectivity for tumor cells by targeting mitochondria [16,20,21]. On the other hand, iridium complexes are very promising alternatives to platinum-based metallo-anticancer agents [22e24].…”