Mitochondria-targeted Anticancer Agents Research Articles

Naphthalene Diimide-Functionalized Half-Sandwich Ru(II) Complexes as Mitochondria-Targeted Anticancer and Antimetastatic Agents.

In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes Ru1-Ru4 bearing the general formula [(η6-arene)RuII(N^N)Cl]PF6, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD+, and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment.

Inducing and monitoring mitochondrial pH changes with an iridium(III) complex via two-photon lifetime imaging.

Real-time monitoring of mitochondrial dynamic changes plays a key role in the development of mitochondria-targeted anticancer theranostic agents. In this work, a pH-responsive and mitochondria-targeted cyclometalated iridium(III) complex MitoIr-NH has been explored as a novel anticancer agent. MitoIr-NH displayed pH-responsive phosphorescence intensity and lifetime, accumulated in mitochondria, showed higher antiproliferative activity and induced a series of mitochondria-related events. Moreover, MitoIr-NH could simultaneously induce mitophagy and quantitatively monitor mitochondrial pH changes through two-photon phosphorescence lifetime imaging microscopy (TPPLIM) in a real-time manner.

The nature compound dehydrocrenatidine exerts potent antihepatocellular carcinoma by destroying mitochondrial complexes in vitro and in vivo.

Cumulative evidence indicates that mitochondria dysfunction plays an important role in tumour treatment. Given the limited efficacy and toxicity of current mitochondria-targeted drugs, research into effective mitochondria-targeted anticancer agentsremains an irresistible general trend. In this study, it was found that dehydrocrenatidine (DEC), a β-carbolin alkaloid isolated from Picrasma quassiodes, displays a promising growth inhibitory effect in vitro and in vivo by inducing apoptosis of hepatocellular carcinoma (HCC) cells. Mechanistically, we provided that the possible target of DEC against HCC cells was determined by isobaric labels for relative and absolute quantification assay and validated them using further experiments. The results suggested that DEC can target and regulate the function of mitochondrial complexes I, III and IV, affecting oxidative phosphorylation and ultimately leading to mitochondrial dysfunction to exert its anti-HCC effects. In addition, the combination of DEC and sorafenib showed a synergistic effect and was also associated with mitochondrial dysfunction. Importantly, DEC did not show significant toxicity in mice. This study provided a new insight into underlying mechanisms in DEC-treated HCC cells, suggesting that DEC might be a mitochondrial targeting lead compound.

Cyclometalated Iridium(Iii) Dithioformic Acid Complexes as Mitochondria-Targeted Imaging and Anticancer Agents

Cyclometalated Iridium(Iii) Dithioformic Acid Complexes as Mitochondria-Targeted Imaging and Anticancer Agents

Brominated cyclometalated iridium(III) complexes for mitochondrial immobilization as potential anticancer agents.

Mitochondria-targeted iridium complexes for anticancer studies have received increasing attention in recent years. Herein, three cyclometalated iridium(III) complexes Ir1-Ir3 [Ir(N^C)2(N^N)](PF6) (N^N = 2,2'-bipyridine (bpy)) or 2-(5-bromopyridin-2-yl)benzo[d]thiazole (bpybt); [N^C = 2-phenylpyridine (ppy) or 2-phenylquinoline (pq) or 2-(4-bromophenyl)benzo[d]thiazole (bpbt)] had been explored as potential mitochondria-targeted anticancer agents. All of the complexes mainly localized in the mitochondria and could be fixed on the mitochondria through a nucleophilic reaction with reactive mitochondrial proteins. Further studies revealed that these complexes showed high anticancer activity, induced mitochondrial depolarization, elevated intracellular reactive oxygen species (ROS) levels, restrained thioredoxin reductase (TrxR) activity, and inhibited the formation of tumor cell colonies and angiogenesis. Further mechanistic studies showed that complex Ir2 could markedly stimulate the activation of caspase-3, regulate the expression of Bax and KI67, and trigger apoptosis.

Conjugation of Natural Triterpenic Acids with Delocalized Lipophilic Cations: Selective Targeting Cancer Cell Mitochondria.

Currently, a new line of research on mitochondria-targeted anticancer drugs is actively developing in the field of biomedicine and medicinal chemistry. The distinguishing features of this universal target for anticancer agents include presence of mitochondria in the overwhelming majority, if not all types of transformed cells, crucial importance of these cytoplasmic organelles in energy production, regulation of cell death pathways, as well as generation of reactive oxygen species and maintenance of calcium homeostasis. Hence, mitochondriotropic anticancer mitocan agents, acting through mitochondrial destabilization, have good prospects in cancer therapy. Available natural pentacyclic triterpenoids are considered promising scaffolds for development of new mitochondria-targeted anticancer agents. These secondary metabolites affect the mitochondria of tumor cells and initiate formation of reactive oxygen species. The present paper focuses on the latest research outcomes of synthesis and study of cytotoxic activity of conjugates of pentacyclic triterpenoids with some mitochondria-targeted cationic lipophilic molecules and highlights the advantages of applying them as novel mitocan agents compared to their prototype natural triterpenic acids.

Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer and antibacterial agents to induce both autophagy and apoptosis

Mitochondrial damage will hinder the energy production of cells and produce excessive ROS (reactive oxygen species), resulting in cell death through autophagy or apoptosis. In this paper, four cyclometalated iridium(III) complexes (Ir1: [Ir(piq)2L]PF6; Ir2: [Ir(bzq)2L]PF6; Ir3: [Ir(dfppy)2L]PF6; Ir4: [Ir(thpy)2L]PF6; piq = 1-phenylisoquinoline; bzq = benzo[h]quinoline; dfppy = 2-(2,4-difluorophenyl)pyridine;thpy = 2-(2-thienyl)pyridine; L = 1,10-phenanthroline-5-amine) were synthesized and characterized. Cytotoxicity tests show that these complexes have excellent cytotoxicity to cancer cells, and mechanism studies indicatethat these complexes can specifically target mitochondria. Complexes Ir1 and Ir2 can damage the function of mitochondria, subsequently increasing intracellular levels of ROS, decreasing MMP (mitochondrial membrane potential), and interfering with ATP energy production, which leads to autophagy and apoptosis. Furthermore, autophagy induced by Ir1 and Ir2 can promote cell death in coordination with apoptosis. Surprisingly, these four complexes also showed moderate antibacterial activity to S. aureusand P. aeruginosa.

Rational design, synthesis and biological evaluation of triphenylphosphonium-ginsenoside conjugates as mitochondria-targeting anti-cancer agents

In anti-cancer therapy, targeting a single gene or a single metabolic pathway usually cannot effectively cure cancer, while targeting cellular mitochondria might be effective based on the role of mitochondria in the occurrence and development of cancer. Anti-cancer study on ginsenosides AD-1, AD-2 and PD have proved that they have broad spectrum anti-cancer activities in vitro and in vivo. However, they are not active at sufficiently low concentration, and their lower selectivity and cell permeability hindered therapeutic applications. In the present study, AD-1, AD-2 and PD are incorporated with triphenylphosphonium at the OH group in C-3 position through different length of alkyl chains, with the aim of targeting mitochondria and improving the efficacy and selectivity of parent compounds. Biological studies suggested that most of the conjugates had enhanced anti-proliferative activity, in particular, conjugate 1f had an IC50 value of 0.76 μM against MCF-7 cells while showed a high degree of selectivity to MCF-7 cells. In addition, 1f was obviously increased accumulation in the mitochondria, and induced apoptosis, elevated reactive oxygen species (ROS) level and caused mitochondrial membrane potential collapse in MCF-7 cells. Further study revealed that ROS-related mitochondrial translocation of p53 was also involved in 1f-induced mitochondrial apoptotic pathway. The results demonstrated that 1f could be a promising lead for the development of mitocans. These findings also provide a reference for the development of ginsenoside for mitochondria-targeted anti-cancer drugs.

Mitochondria-targeted phosphorescent cyclometalated iridium(III) complexes: synthesis, characterization, and anticancer properties.

Cyclometalated iridium(III) complexes represent a promising approach to developing new anticancer metallodrugs. In this work, three phosphorescent cyclometalated iridium(III) complexes Ir1-Ir3 have been explored as mitochondria-targeted anticancer agents. All three complexes display higher antiproliferative activity than cisplatin against the cancer cells screened, and with the IC50 values ranging from 0.23 to 5.6μM. Colocalization studies showed that these complexes are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy through initiating a series of events related to mitochondrial dysfunction, including depolarization of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS) levels, and induction of apoptosis. Mitochondria-targted cyclometalated iridium complexes induce apoptosis through depolarized mitochondria, elevation of intracellular ROS and activated caspase.

Transition metal complexes with 6,7-dichloro-5,8-quinolinedione as mitochondria-targeted anticancer agents

Herein, a series of transition metal complexes, [Zn(DQ)2(CH3OH)2] (1), [Zn(DMQ)2(CH3OH)2] (2), [Co(DQ)2(CH3OH)2] (3), [Co(DMQ)2(CH3OH)2] (4), [Ni(DQ)2(CH3OH)2] (5), [Cu(DMQ)2(CH3OH)2] (6), [Mn(DQ)2(H2O)2] (7) and [Mn(DMQ)2(H2O)2] (8), containing 6,7-dichloro-5,8-quinolinedione (DQ) and 6,7-dichloro-2-methyl-5,8-quinolinedione (DMQ) ligands have been synthesized and characterized as potential antitumor agents. These complexes 1–8 exhibited evident anti-tumor activity in HeLa (cervical), MCF-7 (breast), Hep-G2 (hepatoma), T-24 (bladder), and SK-OV-3 (ovarian) human cancer cells. Interestingly, complexes 1–8 showed higher cytotoxicity than cisplatin against human cervical HeLa cells, and less cytotoxicity on the HL-7702 nontumorigenic cells. Mechanism studies suggested that complexes 1 and 2 arrested the cell cycle in the G1 phase and induced cancer cell death through mitochondrial dysfunction pathways. The cytotoxicity of 2 was higher than that of 1. The different biological behavior of 1 and 2 may correlate with the presence of a 2-methyl group in 6,7-dichloro-2-methyl-5,8-quinolinedione (DMQ) ligand. In general, our study demonstrated that Zn(II) complex 2 with 6,7-dichloro- 2-methyl-5,8-quinolinedione showed high potential to be developed as a mitochondria-targeted metal antitumor agent.

Cyclometallated iridium(III)-5-bromo-8-quinolinol complexes as mitochondria-targeted anticancer agents

Here, two new cyclometallated iridium(III) complexes, [Ir(BrQ)(L1)2] (Ir-1) and [Ir(BrQ)(L2)2] (Ir-2) containing 5-bromo-8-quinolinol (H-BrQ), 2-phenylpyridine (H-L1) and 1-phenylpyrazole (H-L2) ligands have been explored as an anticancer agents targeting mitochondria. The cyclometallated iridium(III) complexes Ir-1 and Ir-2 exhibits excellent antineoplastic activity and promising selectivity towards cervical carcinoma HeLa, with IC50 values were 3.53 ± 0.44 μM and 0.50 ± 0.39 μM, as compared to the human HL-7702 healthy cells and cisplatin-resistant SK-OV-3/DDP cancer cells. Flow cytometry confirmed that cervical carcinoma HeLa cells were caused apoptosis after being treatment with Ir-1 and Ir-2. Along with the decrease of mitochondrial membrane potential (MMP) level, massive release of cytochrome c (cyto C), clear changes in apoptosis-associated proteins, and triggers caspase-mediated mitochondrial dysfunction apoptosis pathways.

Synthesis, photophysical and anticancer properties of mitochondria-targeted phosphorescent cyclometalated iridium(III) N-heterocyclic carbene complexes

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.

Cyclometalated iridium(III)-guanidinium complexes as mitochondria-targeted anticancer agents

Guanidinium-functionalized molecules are commonly studied for their use as pharmaceutically active compounds and drugs carriers. Herein, four cyclometalated iridium(III) complexes containing guanidinium ligands have been synthesized and characterized as potential anticancer agents. These complexes exhibit moderate antitumor activity in HeLa, MCF-7, HepG2, CNE-2, and A549 human tumor cells. Interestingly, all complexes showed higher cytotoxicity than cisplatin against a cisplatin-resistant cell line A549R, and less cytotoxicity on the nontumorigenic LO2 cells. Intracellular distribution studies suggest that these complexes are selectively localized in the mitochondria. Mechanism studies indicate that these complexes arrested the cell cycle in the G0/G1 phase and can influence mitochondrial integrity, inducing cancer cell death through reactive oxygen species (ROS)-dependent pathways.

Cyclometalated iridium(iii) N-heterocyclic carbene complexes as potential mitochondrial anticancer and photodynamic agents.

Metal N-heterocyclic carbene (NHC) complexes represent a promising class of anticancer therapeutic agents. In this work, four cyclometalated iridium(iii) complexes (Ir1-Ir4) containing N-heterocyclic carbene ligands have been explored as mitochondrial anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, can quickly penetrate into A549 cells and are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by increasing the intracellular ROS level, reducing the mitochondrial membrane potential (MMP) and inducing apoptosis. Additionally, Ir1-Ir4 exhibited two orders of magnitude higher cytotoxicity upon irradiation at 450 nm LED light. Our work provides a strategy for the design of highly effective anticancer photodynamic therapeutic agent based phosphorescent iridium complexes.

Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents.

Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2′-bipyridine-4,4′-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes.

Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy.

Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc.

Cyclometalated iridium(III) complexes as mitochondria-targeted anticancer agents.

Four cyclometalated iridium(III) complexes [Ir(dfppy)2(L)](+) (dfppy=2-(2,4-difluorophenyl)pyridine, L=6-(pyridin-2-yl)-1,3,5-triazine-2,4-diamine, Ir1; 6-(isoquinolin-1-yl)-1,3,5-triazine-2,4-diamine, Ir2; 6-(quinolin-2-yl)-1,3,5-triazine-2,4-diamine, Ir3; 6-(isoquinolin-3-yl)-1,3,5-triazine-2,4-diamine, Ir4) have been synthesized and characterized. Distinct from cisplatin, Ir1-Ir4 could specifically target mitochondria and induced apoptosis against various cancer cell lines, especially for cisplatin resistant cells. ICP-MS results indicated that Ir1-Ir4 were taken up via different mechanism for cancer cells and normal cells, which resulted in their high selectivity. The structure-activity relationship and signaling pathways were also discussed.

Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents.

Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy.