👤 Wang KN

Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and has a high recurrence rate and treatment resistance. Recent results indicate that mitochondrial metabolism influences the therapeutic outcomes of BC. Mitochondria-targeted photosensitizer (PS) is a promising anticancer therapeutic approach that may overcome the limitations of conventional BC treatments. Herein, two mitochondria-targeted iridium(III) PSs, Ir-Mito1 and Ir-Mito2, have been designed for BC treatment. Mechanically, Ir-Mito2 induced a decrease in mitochondrial membrane potential via white light activation, further triggering a reduction of the B-cell lymphoma 2 protein (Bcl-2)/Bcl-associated X protein (Bax) ratio and increment of cleaved caspase3. Meanwhile, the reduction of glutathione, deactivation of glutathione peroxidase 4 (GPX4), increase of acyl-CoA synthetase long chain family member 4 (ACSL4), and accumulation of lipid peroxide resulted in synergistically activating of ferroptosis and apoptosis. The results demonstrated that Ir-Mito2 exhibited excellent antitumor efficacy with superior biosafety in vivo. This work on light-activated and mitochondrial-targeted PS provides an innovative therapeutic platform for BC. Show less

Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth. Show less

A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation, causing dual-mode (oxygen-independent and oxygen-dependent) photodynamic damage in mitochondria and killing cancer cells effectively even under hypoxic conditions. Show less

The development of iridium complexes as potent anticancer agents has received increasing attention in recent years. In this study, four cyclometalated Ir(iii) complexes with good photophysical properties and potent anticancer activity have been synthesized and characterized. They are taken up by human lung adenocarcinoma A549 cells very quickly and specifically target mitochondria. Mechanism studies reveal that one of them, namely IrM2, induces paraptosis accompanied by excessive mitochondria-derived cytoplasmic vacuoles. Meanwhile, IrM2 affects the ubiquitin-proteasome system (UPS) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, IrM2 rapidly induces a series of mitochondria-related dysfunctional events, including the loss of mitochondrial membrane potential, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The rapid loss of mitochondrial functions, elevation of ROS and impairment of the UPS induced by IrM2 lead to the collapse of mitochondria and the subsequent cytoplasmic vacuolation before the cells are ready to start the mechanisms of apoptosis and/or autophagy. Among the ROS, superoxide anion radicals play a critical role in IrM2-mediated cell death. In vivo studies reveal that IrM2 can significantly inhibit tumor growth in a mouse model. This work gives useful insights into the design and anticancer mechanisms of new metal-based anticancer agents. Show less

Described is a novel organorhodium(I) complex that is cytotoxic to the colon cancer cell line HCT116 and alters cell migration, DNA replication, and DNA condensation. Most importantly, the mechanism observed is not seen for the parent organorhodium dimer complex [{RhCl(COD)}2], RhCl3, or the free ligand/proligands (COD and 1-(n)butyl-3-methylimidazolium chloride). Thus, the activity of this organorhodium complex is attributable to its unique structure. Show less

A series of mononuclear Ru(II) complexes of the type [Ru(S)(2)(K)](2+), where S = 1,10-phenanthroline/2,2'-bipyridine and K = 4-OH-btsz, 4-CH(3)-btsz, 3,4-di-OCH(3)-btsz, 4-OH-binh, 4-CH(3)-binh, 3,4-di-OCH(3)-binh, were prepared and characterized by elemental analysis, FTIR, (1)H-NMR, and mass spectroscopy. The complexes displayed metal-ligand charge transfer (MLCT) transitions in the visible region. These ligands formed bidentate octahedral ruthenium complexes. The title complexes were evaluated for their in vivo anticancer activity against a transplantable murine tumor cell line, Ehrlisch's ascites carcinoma (EAC), and in vitro cytotoxic activity against human cancer cell lines Molt 4/C(8) and CEM and murine tumor cell line L1210. The ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these complexes prolonged the life span of mice bearing EAC tumors by 10-52%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 muM against Molt 4/C(8), 0.16 to 19 microM against CEM, and 0.75 to 32 microM against L1210. Show less