ABSTRACT
Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.
Subject(s)
Copper , Glutathione , Homeostasis , Oxidation-Reduction , Animals , Mice , Humans , Glutathione/metabolism , Mice, Inbred C57BL , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Oxidative Stress/drug effects , Drug Synergism , Immunogenic Cell Death/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Ferroptosis/drug effects , Reactive Oxygen Species/metabolism , Colorectal Neoplasms/immunology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolismABSTRACT
Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex (1a) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a, the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.
Subject(s)
Antineoplastic Agents , Immunogenic Cell Death , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Iridium/pharmacology , Unfolded Protein ResponseABSTRACT
A novel and efficient protocol for the regioselective synthesis of 3-styrylcoumarins from readily available cinnamic acids and coumarins is presented. The reaction proceeds via a decarboxylative cross-coupling mediated by a catalytic amount of Pd(OAc)2, with Ag2CO3 as an oxidant, and with 1,10-phenanthroline as a ligand. A plausible reaction mechanism for this process is depicted, and the resulting 3-styrylcoumarins show excellent fluorescence quantum yields.
ABSTRACT
The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid Câ§N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.
Subject(s)
Antineoplastic Agents , Ferroptosis , Isoquinolines , Triple Negative Breast Neoplasms , Ferroptosis/drug effects , Humans , Isoquinolines/pharmacology , Isoquinolines/chemistry , Isoquinolines/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Animals , Female , Cell Line, Tumor , Ferritins/metabolism , Autophagy/drug effects , Mice , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Alkaloids/pharmacology , Alkaloids/chemistry , Alkaloids/chemical synthesis , Structure-Activity Relationship , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects , Mice, NudeABSTRACT
N-linked glycosylation of proteins is one of the post-translational modifications (PTMs) that shield tumor antigens from immune attack. Signaling lymphocytic activation molecule family 7 (SLAMF7) suppresses cancer cell phagocytosis and is an ideal target under clinical development. PTM of SLAMF7, however, remains less understood. In this study, we investigated the role of N-glycans on SLAMF7 in breast cancer progression. We identified seven N-linked glycosylation motifs on SLAMF7, which are majorly occupied by complex structures. Evolutionally conserved N98 residue is enriched with high mannose and sialylated glycans. Hyperglycosylated SLAMF7 was associated with STT3A expression in breast cancer cells. Inhibition of STT3A by a small molecule inhibitor, N-linked glycosylation inhibitor-1 (NGI-1), reduced glycosylation of SLAMF7, resulting in enhancing antibody affinity and phagocytosis. To provide an on-target effect, we developed an antibody-drug conjugate (ADC) by coupling the anti-SLAMF7 antibody with NGI-1. Deglycosylation of SLAMF7 increases antibody recognition and promotes macrophage engulfment of breast cancer cells. Our work suggests deglycosylation by ADC is a potential strategy to enhance the response of immunotherapeutic agents.
ABSTRACT
BACKGROUND: Despite clinical success with anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines has been compromised by rapidly spreading SARS-CoV-2 variants. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host's immune response and attenuate antibody efficiency. However, it remains unclear if targeting glycosylation on viral spike protein can impair infectivity of SARS-CoV-2 and its variants. METHODS: We adopted flow cytometry, ELISA, and BioLayer interferometry approaches to assess binding of glycosylated or deglycosylated spike with ACE2. Viral entry was determined by luciferase, immunoblotting, and immunofluorescence assays. Genome-wide association study (GWAS) revealed a significant relationship between STT3A and COVID-19 severity. NF-κB/STT3A-regulated N-glycosylation was investigated by gene knockdown, chromatin immunoprecipitation, and promoter assay. We developed an antibody-drug conjugate (ADC) that couples non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) to specifically target SARS-CoV-2-infected cells. FINDINGS: The receptor binding domain and three distinct SARS-CoV-2 surface N-glycosylation sites among 57,311 spike proteins retrieved from the NCBI-Virus-database are highly evolutionarily conserved (99.67%) and are involved in ACE2 interaction. STT3A is a key glycosyltransferase catalyzing spike glycosylation and is positively correlated with COVID-19 severity. We found that inhibiting STT3A using N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 infectivity and that of its variants [Alpha (B.1.1.7) and Beta (B.1.351)]. Most importantly, 4G10-ADC enters SARS-CoV-2-infected cells and NGI-1 is subsequently released to deglycosylate spike protein, thereby reinforcing the neutralizing abilities of antibodies, vaccines, or convalescent sera and reducing SARS-CoV-2 variant infectivity. INTERPRETATION: Our results indicate that targeting evolutionarily-conserved STT3A-mediated glycosylation via an ADC can exert profound impacts on SARS-CoV-2 variant infectivity. Thus, we have identified a novel deglycosylation method suitable for eradicating SARS-CoV-2 variant infection in vitro. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
Subject(s)
Benzamides/pharmacology , COVID-19 Drug Treatment , Glycosylation/drug effects , Hexosyltransferases/antagonists & inhibitors , Membrane Proteins/antagonists & inhibitors , Sulfonamides/pharmacology , Virus Internalization/drug effects , A549 Cells , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Cell Line , HEK293 Cells , Hexosyltransferases/metabolism , Humans , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , SARS-CoV-2/growth & development , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
The title mixed-ligand copper(I) complex, [Cu(C(18)H(13)N(4)O(5)S)(C(18)H(15)P)(2)], was synthesized via solvothermal reaction of [Cu(PPh(3))(2)(MeCN)(2)]ClO(4) and sulfasalazine [systematic name: 2-hydr-oxy-5-(2-{4-[(2-pyridylamino)sulfon-yl]phen-yl}diazen-yl)benzoic acid]. The mononuclear complex displays a trigonal coordination geometry for the Cu(I) atom, which is surrounded by two P-atom donors from two different PPh(3) ligands and one O-atom donor from the monodentate carboxyl-ate group of the sulfasalazinate ligand. The latter ligand is found in a zwitterionic form, with a deprotonated amine N atom and a protonated pyridine N atom. Such a feature was previously described for free sulfasalazine. The crystal structure is stabilized by C-Hâ¯O, C-Hâ¯N, N-Hâ¯N and O-Hâ¯O hydrogen bonds.
ABSTRACT
Two copper complexes, Cu1 (CuL1Cl2, L1 = 2-(6,7-dimethoxyisoquinolin-1-yl) aniline) and Cu2 (CuL2Cl2, L2 = 2-(6-methoxyisoquinolin-1-yl) aniline), were synthesized and characterized. These complexes exhibited high cytotoxic activity toward different cancer cell lines, including the A549 lung cancer cell line, and low cytotoxicity toward normal human cells. Mechanistic studies have shown that these complexes induce bimodal death of cancer cells through apoptosis and autophagy, including the activation of apoptotic and autophagic cell signaling pathways. In addition, Cu1 and Cu2 interacted with calf thymus DNA (ct-DNA) via an intercalative binding mode. The different biological behaviors of these copper complexes could be attributed to the presence of electron-donating methoxy groups on the ligands. Cu1 and Cu2 effectively inhibited tumor growth in a xenografted mouse model bearing A549 cells but exhibited lower in vivo toxicity than cisplatin. Thus, Cu1 and Cu2 can be developed as potential anticancer agents.
Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Coordination Complexes/pharmacology , Copper/pharmacology , A549 Cells , Animals , Binding, Competitive , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , MAP Kinase Signaling System/drug effects , Mice , Reactive Oxygen Species/metabolism , Xenograft Model Antitumor AssaysABSTRACT
An efficient strategy for the synthesis of benzofuro[2,3- b]pyrazines was developed. These tricyclic scaffolds were formed through a multistep cascade sequence, which includes double insertion of isonitriles and chemoselective bicyclization. In this reaction, a nanopalladium was used as a recyclable catalyst. Product 3w exhibited excellent anticancer activity toward T-24 (IC50 = 12.5 ± 0.9 µM) and HeLa (IC50 = 14.7 ± 1.6 µM) cells. We also explored the action mechanism of 3w on T-24 cells.
Subject(s)
Nitriles/chemistry , Nitriles/chemical synthesis , Phenols/chemistry , Phenols/chemical synthesis , Pyrazines/chemistry , Pyrazines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Catalysis , Chemistry Techniques, Synthetic , PorosityABSTRACT
A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Esters/pharmacology , Lung Neoplasms/drug therapy , Organophosphonates/pharmacology , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents, Immunological/chemistry , Cell Death/drug effects , Esters/chemistry , Humans , Ligands , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Organophosphonates/chemistry , Organoplatinum Compounds/chemistryABSTRACT
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands. In comparison to cisplatin, n-Mon-Pt-1 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that n-Mon-Pt-1 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition, ROS release and an ER stress response, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, n-Mon-Pt-1 exhibits lower acute toxicity and better anticancer activity in a murine tumor model.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Gene Expression Regulation, Neoplastic , Lung Neoplasms/drug therapy , Organoplatinum Compounds/pharmacology , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/genetics , Autophagy/genetics , Cell Line , Cell Line, Tumor , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Eukaryotic Initiation Factor-2/genetics , Eukaryotic Initiation Factor-2/metabolism , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Organoplatinum Compounds/chemical synthesis , Quinolines/chemistry , Reactive Oxygen Species/agonists , Reactive Oxygen Species/metabolism , Signal Transduction , Thioredoxin Reductase 1/genetics , Thioredoxin Reductase 1/metabolism , Transcription Factor CHOP/genetics , Transcription Factor CHOP/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , eIF-2 Kinase/genetics , eIF-2 Kinase/metabolismABSTRACT
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1Cl]Cl [L1 = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2Cl]Cl [L2 = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2). In comparison to cisplatin, Mon-Pt-2 exhibited a greater in vitro cytotoxicity, was more effective in resistant cells and elicited a better anticancer effect. Mechanistic experiments indicate that Mon-Pt-2 mainly accumulates in mitochondria, and stimulates significant TrxR inhibition ROS release and an ER stress response, mediated by mitochondrial dysfunction, ultimately resulting in a simultaneous induction of apoptosis and autophagy. Importantly, compared to cisplatin, Mon-Pt-2 exhibits lower acute toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Mon-Pt-2 is the first mono-functional platinum complex inducing pro-death autophagy and apoptosis of cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Endoplasmic Reticulum/drug effects , Mitochondria/drug effects , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Endoplasmic Reticulum Stress/drug effects , Humans , Mice , Mice, Inbred Strains , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Agents inducing both apoptosis and autophagic death can be effective chemotherapeutic drugs. In our present work, we synthesized two organometallic gold(III) complexes harboring C^N ligands that structurally resemble tetrahydroisoquinoline (THIQ): Cyc-Au-1 (AuL1Cl2, L1 = 3,4-dimethoxyphenethylamine) and Cyc-Au-2 (AuL2Cl2, L2 = methylenedioxyphenethylamine). In screening their in vitro activity, we found both gold complexes exhibited lower toxicity, lower resistance factors, and better anticancer activity than those of cisplatin. The organometallic gold(III) complexes accumulate in mitochondria and induce elevated ROS and an ER stress response through mitochondrial dysfunction. These effects ultimately result in simultaneous apoptosis and autophagy. Importantly, compared to cisplatin, Cyc-Au-2 exhibits lower toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Cyc-Au-2 is the first organometallic Au(III) compound that induces apoptosis and autophagic death. On the basis of our results, we believe Cyc-Au-2 to be a promising anticancer agent or lead compound for further anticancer drug development.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Coordination Complexes/pharmacology , Endoplasmic Reticulum Stress/drug effects , Tetrahydroisoquinolines/pharmacology , A549 Cells , Adenocarcinoma, Bronchiolo-Alveolar/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Coordination Complexes/toxicity , Drug Screening Assays, Antitumor , Humans , Ligands , Male , Mice, Nude , Mitochondria/drug effects , Molecular Structure , Reactive Oxygen Species/metabolism , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/therapeutic use , Tetrahydroisoquinolines/toxicity , Xenograft Model Antitumor AssaysABSTRACT
Lysicamine is a natural oxoaporphine alkaloid, which isolated from traditional Chinese medicine (TCM) herbs and has been shown to possess cytotoxicity to hepatocarcinoma cell lines. Reports on its antitumor activity are scarce because lysicamine occurs in plants at a low content. In this work, we demonstrate a facile concise total synthesis of lysicamine from simple raw materials under mild reaction conditions, and the preparation of the Ru(II), Rh(III), Mn(II) and Zn(II) complexes 1-4 of lysicamine (LY). All the compounds were fully characterized by elemental analysis, IR, ESI-MS, 1H and 13C NMR, as well as single-crystal X-ray diffraction analysis. Compared with the free ligand LY, complexes 2 and 3 exhibited superior in vitro cytotoxicity against HepG2 and NCI-H460. Mechanistic studies indicated that 2 and 3 blocked the cell cycle in the S phase by decreasing of cyclins A2/B1/D1/E1, CDK 2/6, and PCNA levels and increasing levels of p21, p27, p53 and CDC25A proteins. In addition, 2 and 3 induced cell apoptosis via both the caspase-dependent mitochondrial pathway and the death receptor pathway. in vivo study showed that 2 inhibited HepG2 tumor growth at 1/3 maximum tolerated dose (MTD) and had a better safety profile than cisplatin.
ABSTRACT
Four µ2-Cl bridged dinuclear metal complexes with isoquinoline ligands, (MPDQ)2Zn2Cl4 (1) (MPDQ=4.5-methylenedioxy-1-pyridinedihydroisoquinoline), (PYP)2Zn2Cl4 (2) (PYP=5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline), (MPDQ)2Mn2Cl4 (3),and (PYP)2Mn2Cl4 (4) were synthesized and characterized. All complexes exhibited strong proliferation inhibition activity against various cancer cells. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. Induction of apoptosis in MGC-803 cells by complex 2 was evidenced by annexin V+/PI- detection and DiD/DAPI staining assay. Further investigation revealed that complex 2 was able to induce intrinsic pathway-dependent apoptosis in cancer cells by triggering DNA damage which was caused by the overproduction of reactive oxygen species. Based on these studies, we suggest that Zn(II) complexes containing isoquinoline ligands can be developed as candidates for anti-cancer chemotherapeutics.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Isoquinolines/chemistry , Manganese/chemistry , Zinc/chemistry , A549 Cells , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the title compound, C16H17NO4S, the heterocyclic ring is almost planar (r.m.s. deviation = 0.007Å) and the dihedral angle between the benzene rings is 28.18â (10)°. The N-C-C-C torsion angle for the central chain is 62.4â (3)°: overall, the mol-ecule has a Z-shape. In the crystal, inversion dimers linked by pairs of N-Hâ¯O hydrogen bonds generate R 2 (2)(8) loops.
ABSTRACT
Three transition metal complexes with isoquinoline derivatives: [(MPDQ)2Zn(C2H5OH)ClO4]ClO4 (1) (MPDQ = 4,5-methylenedioxy-1-pyridinedihydroisoquinoline), [(PYP)2Zn(H2O)](ClO4)2 (2) (PYP = 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline) and [(MPDQ)2Ni(CH3OH)ClO4]ClO4 (3) were synthesized and fully characterized. All complexes exhibited strong proliferation inhibition activity against various tested cancer cells with high selectivity to tumour and normal cells. BEL-7404 cells were found most sensitive to complex 2 by inducing apoptosis. The process involved the mitochondrial membrane potential depolarization, PARP-proteins cleavage, Bcl-2, p53, p21 expression and caspase family members' activation. Taking these findings into account, it can propose that complex 2 induce cancer cell apoptosis via mitochondrial pathways. The interaction of complex 2 with DNA investigated by fluorescence, CD and viscosity indicated that complex 2 interact with DNA mainly via intercalation.
Subject(s)
Antineoplastic Agents/pharmacology , Isoquinolines/pharmacology , Nickel/pharmacology , Organometallic Compounds/pharmacology , Zinc/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Isoquinolines/chemistry , Membrane Potential, Mitochondrial/drug effects , Models, Molecular , Molecular Structure , Nickel/chemistry , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity Relationship , Zinc/chemistryABSTRACT
[Pt(Q)2] (1) and [Pt(MQ)2] (2) exhibited enhanced cytotoxicity against BEL-7404, Hep-G2, NCI-H460, T-24, A549 tumor cells but low cytotoxicity on normal HL-7702 cells. 1 and 2 could cause the cell cycle arrest in G2 and S phase, respectively. While pifithrin-α, a specific p53 inhibitor, induced cell cycle arrest in G1 phase. Although 1, 2 and pifithrin-α caused serious inhibition on p53, 1 and 2 significantly cause the loss of mitochondrial membrane potential and increase of the reactive oxygen species level, cytochrome c, apaf-1 and caspase-3/9 ratio in BEL-7404 cells. 1 and 2 may trigger the cell apoptosis through a mitochondrial dysfunction pathway whereas pifithrin-α does not. The interactions of 1 and 2 with DNA are most probably via an intercalation.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Organoplatinum Compounds/pharmacology , Oxyquinoline/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Structure-Activity RelationshipABSTRACT
A new platinum(II) complex of [Pt(II)(L) (pn)]Cl·2H2O (1) (pn = 1,3-propanediamine) with 2-(4-methoxy-phenyl)imidazo [4,5-f]-[1,10]phenanthrolin (H-L) was synthesized and characterized. In complex 1, the platinum adopts a four-coordinated square planar geometry. Complex 1 exhibited selective cytotoxicity against NCI-H460, BEL-7402, SK-OV-3, SK-OV-3/DDP and HeLa cell lines with IC50 values in the micromolar range (9.7-35.8 µM), but low cytotoxicity toward normal human liver HL-7702 cells. Complex 1 caused HeLa cell cycle arrest at S phase and it induced HeLa apoptosis by the activation of caspase-3/9. Various experiments showed that complex 1 preferred to bind with G-quadruplex in c-myc. Taken together, we found that complex 1 exerted its antitumor activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and activation of caspase-3/9.
Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Organoplatinum Compounds/pharmacology , Phenanthrolines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Imidazoles/chemistry , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Phenanthrolines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.