ABSTRACT
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
Subject(s)
Antineoplastic Agents , Rhodium , Wnt Signaling Pathway , Rhodium/chemistry , Rhodium/pharmacology , Animals , Wnt Signaling Pathway/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Humans , Mice , beta Catenin/metabolism , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Mice, Inbred C57BLABSTRACT
Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.
Subject(s)
Antineoplastic Agents , Cell Movement , Coordination Complexes , Ruthenium , Humans , Cell Line, Tumor , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Ruthenium/chemistry , Ruthenium/pharmacology , Ruthenium/therapeutic use , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Cell Proliferation/drug effects , Neoplasm Metastasis/prevention & control , Neoplasm Metastasis/drug therapy , Cell Adhesion/drug effectsABSTRACT
Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo. These emerging anticancer agents, mixed chelate copper(II) compounds, induce apoptosis by generating reactive oxygen species (ROS) and causing DNA damage. Whole-transcriptome analysis via gene expression arrays indicated that subtoxic concentrations of CasIIIia upregulate genes involved in metal response mechanisms. Casiopeínas® reduced TNBC cell viability dose-dependently and more efficiently than Cisplatin. At subtoxic concentrations (IC20), they inhibited random and chemotactic migration of MDA-MB-231 and 4T1 cells by 50-60%, similar to Cisplatin, as confirmed by transcriptome analysis. In vivo, CasIIIia and Cisplatin significantly reduced tumor growth, volume, and weight in a syngeneic breast cancer model with 4T1 cells. Furthermore, both compounds significantly decreased metastatic foci in treated mice compared to controls. Thus, CasIIIia and CasIIgly are promising chemotherapeutic candidates against TNBC.
Subject(s)
Antineoplastic Agents , Copper , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Animals , Humans , Female , Copper/chemistry , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Chelating Agents/pharmacology , Apoptosis/drug effects , Xenograft Model Antitumor Assays , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Cell Movement/drug effects , Reactive Oxygen Species/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Mice, Inbred BALB C , DNA Damage/drug effectsABSTRACT
Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.
Subject(s)
Acetylcholinesterase , Butyrylcholinesterase , Cholinesterase Inhibitors , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Animals , Humans , Butyrylcholinesterase/metabolism , Butyrylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Acetylcholinesterase/chemistry , Ruthenium/chemistry , Ruthenium/pharmacology , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Horses , Drug Evaluation, PreclinicalABSTRACT
This study investigates the potential of using ionic liquids as cosolvents to enhance the solubility and activity of poorly soluble rhodium(III) complexes, particularly those with diene, pyridine derivatives, and camphor-derived bis-pyrazolylpyridine ligands, in relation to 5'-GMP, CT-DNA, and HSA as well as their biological activity. Findings indicate that ionic liquids significantly increase the substitution activity of these complexes toward 5'-GMP while only marginally affecting DNA/HSA binding affinities with molecular docking, further confirming the experimental results. Lipophilicity assessments indicated good lipophilicity. Notably, cytotoxicity studies show that Rh2 is selectively effective against HeLa cancer cells, with IL1 and IL10 modulating the cytotoxic effects. Redox evaluations indicate that rhodium complexes induce oxidative stress in cancerous cells while maintaining redox balance in noncancerous cells. By elucidating the role of ionic liquids in modulating these effects, the study proposes a promising avenue for augmenting the efficacy and selectivity of cancer treatments, thus opening new horizons in cancer therapeutics.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ionic Liquids , Rhodium , Humans , Ionic Liquids/chemistry , Ionic Liquids/pharmacology , Ionic Liquids/chemical synthesis , Rhodium/chemistry , Rhodium/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Molecular Docking Simulation , HeLa Cells , Chelating Agents/chemistry , Chelating Agents/pharmacology , Chelating Agents/chemical synthesis , DNA/metabolism , DNA/chemistry , Structure-Activity Relationship , Solubility , Neoplasms/drug therapy , Neoplasms/pathology , Drug Screening Assays, Antitumor , Serum Albumin, Human/chemistry , Serum Albumin, Human/metabolismABSTRACT
Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so â¼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Osteosarcoma , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Animals , Structure-Activity Relationship , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Coordination Complexes/chemistryABSTRACT
Cancer is a significant global health issue. Platinum-based chemotherapy drugs, including cisplatin, are crucial in clinical anti-cancer treatment. However, these drugs have limitations such as drug resistance, non-specific distribution, and irreversible toxic and side effects. In recent years, the development of metal-based agents has led to the discovery of other anti-cancer effects beyond chemotherapy. Precise spatiotemporal controlled external irradiation can activate metal-based agents at specific sites and play a different role from traditional chemotherapy. These strategies can not only enhance the anti-cancer efficiency, but also show fewer side effects and non-cross-drug resistance, which are ideal approaches to solve the problems caused by traditional platinum-based chemotherapy drugs. In this review, we focus on various metal-based agent-mediated cancer therapies that are activated by three types of external irradiation: near-infrared (NIR) light, ultrasound (US), and X-ray, and give some prospects. We hope that this review will promote the generation of new kinds of metal-based anti-cancer agents.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Infrared Rays , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Coordination Complexes/pharmacology , Metals/chemistry , X-Rays , AnimalsABSTRACT
Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Copper , Lung Neoplasms , Thiosemicarbazones , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/therapeutic use , Humans , Copper/chemistry , Animals , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Mice , Mice, Nude , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/pathology , Cell Line, Tumor , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , A549 Cells , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Signal Transduction/drug effects , Structure-Activity Relationship , Hemolysis/drug effects , Drug Screening Assays, Antitumor , Mice, Inbred BALB CABSTRACT
The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.
Subject(s)
Radium , Radium/chemistry , Radium/therapeutic use , Humans , Radioisotopes/chemistry , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Barium/chemistry , Alpha Particles/therapeutic use , Chelating Agents/chemistry , Chelating Agents/therapeutic use , Neoplasms/drug therapy , Theranostic Nanomedicine/methods , Metals, Alkaline Earth/chemistry , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/therapeutic useABSTRACT
This Special Issue (SI), "Emerging Topics in Metal Complexes: Pharmacological Activity", includes reports updating our knowledge on metals with multidirectional biological properties and metal-containing compounds/complexes for their potential therapeutic applications, with a focus on strategies improving their pharmacological features [...].
Subject(s)
Coordination Complexes , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Humans , Metals/chemistry , AnimalsABSTRACT
Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with inâ situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both inâ vitro and inâ vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.
Subject(s)
Aluminum , Antineoplastic Agents , Cellular Senescence , Ethylenediamines , Platinum , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Ethylenediamines/chemistry , Ethylenediamines/pharmacology , Cellular Senescence/drug effects , Platinum/chemistry , Platinum/pharmacology , Aluminum/chemistry , Aluminum/pharmacology , Animals , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Neoplasms/drug therapy , Neoplasms/pathology , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/chemistryABSTRACT
Supramolecular coordination complexes (SCCs) are predictable and size-tunable supramolecular self-assemblies constructed through directional coordination bonds between readily available organic ligands and metallic receptors. Based on planar and 3D structures, SCCs can be mainly divided into two categories: metallacycles (e.g., rhomboidal, triangular, rectangular, and hexagonal) and metallacages (e.g., tetrahedral, hexahedral, and dodecahedral). The directional coordination bonds enable the efficient formation of metallacycles and metallacages with well-defined architectures and geometries. SCCs exhibit several advantages, including good directionality, strong interaction force, tunable modularity, and good solution processability, making them highly attractive for biomedical applications, especially in cellular imaging and cancer therapy. Compared with their molecular precursors, SCCs demonstrate enhanced cellular uptake and a strengthened tumor accumulation effect, owing to their inherently charged structures. These properties and the chemotherapeutic potential inherent to organic platinum complexes have promoted their widespread application in antitumor therapy. Furthermore, the defined structures of SCCs, achieved via the design modification of assembly elements and introduction of different functional groups, enable them to combat malignant tumors through multipronged treatment modalities. Because the development of cancer-treatment methodologies integrated in clinics has evolved from single-modality chemotherapy to synergistic multimodal therapy, the development of functional SCCs for synergistic cancer therapy is crucial. While some pioneering reviews have explored the bioapplications of SCCs, often categorized by a specific function or focusing on the specific metal or ligand types, a comprehensive exploration of their synergistic multifunctionality is a critical gap in the current literature.In this Account, we focus on platinum-based SCCs and their applications in cancer therapy. While other metals, such as Pd-, Rh-, Ru-, and Ir-based SCCs, have been explored for cancer therapy by Therrien and Casini et al., platinum-based SCCs have garnered significant interest, owing to their unique advantages in antitumor therapy. These platinum-based SCCs, which enhance antitumor efficacy, are considered prominent candidates for cancer therapies owing to their desirable properties, such as potent antitumor activity, exceptionally low systemic toxicity, active tumor-targeting ability, and enhanced cellular uptake. Furthermore, diverse diagnostic and therapeutic modalities (e.g., chemotherapy, photothermal therapy, and photodynamic therapy) can be integrated into a single platform based on platinum-based SCCs for cancer therapy. Consequently, herein, we summarize our recent research on platinum-based SCCs for synergistic cancer therapy with particular emphasis on the cooperative interplay between different therapeutic methods. In the Conclusions section, we present the key advancements achieved on the basis of our research findings and propose future directions that may significantly impact the field.
Subject(s)
Coordination Complexes , Neoplasms , Humans , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Coordination Complexes/chemistry , Neoplasms/drug therapy , Platinum/chemistryABSTRACT
Copper is a necessary micronutrient for maintaining the well-being of the human body. The biological activity of organic ligands, especially their anticancer activity, is often enhanced when they coordinate with copper(I) and (II) ions. Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and paraptosis. Some of the copper complexes are currently being evaluated in clinical trials for their ability to map tumor hypoxia in various cancers, including locally advanced rectal cancer and bulky tumors. Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy. Despite the promising anticancer activity of copper-based compounds, their use in clinical trials is subject to certain limitations. Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes.
Subject(s)
Antineoplastic Agents , Copper , Neoplasms , Humans , Copper/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/pathology , Animals , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Coordination Complexes/chemistryABSTRACT
The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.
Subject(s)
Angiogenesis Inhibitors , Antineoplastic Agents , Apoptosis , Coordination Complexes , Phenanthrolines , Triple Negative Breast Neoplasms , Apoptosis/drug effects , Humans , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Animals , Phenanthrolines/pharmacology , Phenanthrolines/chemistry , Phenanthrolines/chemical synthesis , Female , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Mice , Cell Line, Tumor , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Drug Synergism , Structure-Activity Relationship , Mice, Inbred BALB C , Drug Screening Assays, AntitumorABSTRACT
FETPY, an organo-diiron(I) complex, showed strong cytotoxicity across a panel of human and mouse cancer cell lines, combined with an outstanding selectivity compared to nonmalignant cells. Enhanced iron uptake in aggressive, low-differentiated cell lines, caused membrane lipid peroxidation, which resulted in ferroptosis in human ovarian cancer cells. FETPY induced significant morphological changes in murine B16-F1 and B16-F10 melanoma cells, leading to senescence and/or trans-differentiation into Schwann-like cells, thus significantly reducing their tumorigenic potential. Additionally, FETPY substantially suppressed tumor growth in low- and high-grade syngeneic melanoma models when administered in a therapeutic regimen. FETPY is featured by satisfactory water solubility (millimolar range), an amphiphilic character (Log Pow = -0.17), and excellent stability in a biological medium (DMEM). These important requisites for drug development are rarely met in iron complexes investigated so far as possible anticancer agents. Overall, FETPY holds promise as a safe and potent targeted antitumor agent.
Subject(s)
Antineoplastic Agents , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Drug Screening Assays, Antitumor , Iron/chemistry , Iron/metabolism , Lipid Peroxidation/drug effects , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Mice, Inbred C57BLABSTRACT
Triple negative breast cancer (TNBCs), known as an immunologically cold tumor, is difficult to completely eliminate with existing monotherapies, let alone metastasis and recurrence. It is urgent to design a rational combination of multiple therapies to programmatically reconstitute tumor microenvironment (TME) and reverse the immune "cold" into "hot" inflammatory tumors to improve the therapeutic effect. Hence, in this work, a multifunctional nanosystem (FeSH NPs) that integrates metal-polyphenol coordination complex as a photothermal agent and polyphenol, salvianolic acid B (SAB) as immunomodulator is designed and fabricated for synergistic photothermal-immunotherapy of TNBCs combined with anti-PD-L1 antibody. Guided by photothermal/photoacoustic dual-mode imaging, photothermal therapy (PTT) caused by FeSH NPs induces immunogenic cell death (ICD) under 808 nm laser irradiation. Subsequently, the loaded SAB is released with the addition of deferoxamine mesylate (DFO) to remodel TME, specifically TGF-ß inhibition and PD-L1 upregulation, and eliminate the primary tumors. The combination of PTT and TME reprogramming by FeSH NPs further synergizes with anti-PD-L1 antibody to eradicate recurrence and inhibit metastasis of TNBCs concurrently. Given the biosafety of FeSH NPs throughout the lifecycle, this work provides a protocol with high clinical translational promise for comprehensive programmed therapeutics of immunologically cold tumors TNBCs.
Subject(s)
B7-H1 Antigen , Immunotherapy , Triple Negative Breast Neoplasms , Tumor Microenvironment , Triple Negative Breast Neoplasms/therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/drug therapy , Animals , Mice , Tumor Microenvironment/drug effects , Humans , Cell Line, Tumor , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Female , Photothermal Therapy/methods , Polyphenols/chemistry , Polyphenols/pharmacology , Multifunctional Nanoparticles/chemistry , Transforming Growth Factor beta/metabolism , Coordination Complexes/chemistry , Coordination Complexes/therapeutic useABSTRACT
A series of rhenium(I) complexes of the type fac-[Re(CO)3(N^N)L]0/+, Re1-Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L = chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. The most active complexes, Re7-Re9, incorporating 4-NMe2py, exhibited remarkable activity in 3D HeLa spheroids. The emission in the red region of Re9, which contains an electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for in vitro and in vivo visualization. Re9 effectivity was tested in two different C. elegans tumoral strains, JK1466 and MT2124, to broaden the oncogenic pathways studied. The results showed that Re9 was able to reduce the tumor growth in both strains by increasing the ROS production inside the cells. Moreover, the selectivity of the compound toward cancerous cells was remarkable as it did not affect neither the development nor the progeny of the nematodes.
Subject(s)
Antineoplastic Agents , Caenorhabditis elegans , Coordination Complexes , Rhenium , Animals , Caenorhabditis elegans/drug effects , Rhenium/chemistry , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Theranostic Nanomedicine , Drug Screening Assays, Antitumor , Cell Proliferation/drug effectsABSTRACT
Metal ions such as iron, zinc, copper, manganese, and calcium are essential for normal cellular processes, including DNA synthesis, enzyme activity, cellular signaling, and oxidative stress regulation. When the balance of metal homeostasis is disrupted, it can lead to various pathological conditions, including cancer. Thus, understanding the role of metal homeostasis in cancer has led to the development of anti-tumor strategies that specifically target the metal imbalance. Up to now, diverse small molecule-based chelators, ionophores, metal complexes, and metal-based nanomaterials have been developed to restore the normal balance of metals or exploit the dysregulation for therapeutic purposes. They hold great promise in inhibiting tumor growth, preventing metastasis, and enhancing the effectiveness of existing cancer therapies. In this review, we aim to provide a comprehensive summary of the strategies employed to modulate the homeostasis of iron, zinc, copper, manganese, and calcium for cancer therapy. Their modulation mechanisms for metal homeostasis are succinctly described, and their recent applications in the field of cancer therapy are discussed. At the end, the limitations of these approaches are addressed, and potential avenues for future developments are explored.
Subject(s)
Homeostasis , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Homeostasis/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Metals/chemistry , Metals/metabolism , Iron/metabolism , Iron/chemistry , Chelating Agents/chemistry , Chelating Agents/therapeutic use , Copper/chemistry , Copper/metabolism , Animals , Coordination Complexes/chemistry , Coordination Complexes/therapeutic use , Manganese/chemistry , Manganese/metabolism , Calcium/metabolismABSTRACT
Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.
Subject(s)
Ferroptosis , Nanomedicine , Neoplasms , Ferroptosis/drug effects , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Nanomedicine/methods , Animals , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic useABSTRACT
Non-platinum metal-based complexes have good potential for cancer treatment. Here, we designed and synthesized five hydrazone copper(II) complexes, [Cu2(HL)2Cl2] 1A, [Cu2(HL)2(NO3)H2O]·NO3 2A, [Cu2(HL)2Br2] 3A, [Cu(L)pyridine] 1B and [Cu(HL)(pyridine)Br] 3B, and evaluated their anti-lung cancer activities. MTT experiments revealed that these copper(II) complexes exhibit higher anticancer activity than cisplatin. Mechanism studies revealed that complex 3A induced G1 phase cell cycle arrest, and induced cell apoptosis via reactive oxygen species (ROS)-mediated mitochondrial dysfunction. Scratch wound healing assay was also performed, revealing that complex 3A have good anti-cell migration activity. Hemolysis assays showed good blood biocompatibility of complex 3A. Furthermore, complex 3A can significantly inhibit the proliferation of A549 3D tumor spheroid. An in vivo anticancer study showed that complex 3A could delays the growth of A549 tumor xenografts with lower systemic toxicity. These results highlight the great possibility of developing highly active copper complexes as anti-lung cancer agents.