Journal of Inorganic Biochemistry最新文献

{"title":"Role of Zn(II) in the aggregation of the 6aJL2R24G protein: Experimental and theoretical approach","authors":"Fernanda Mata-Salgado ,&nbsp;Alan Morales-Ortiz ,&nbsp;Cesar Millan-Pacheco ,&nbsp;Nina Pastor ,&nbsp;Lina Rivillas-Acevedo","doi":"10.1016/j.jinorgbio.2025.113012","DOIUrl":"10.1016/j.jinorgbio.2025.113012","url":null,"abstract":"<div><div>Light chain amyloidosis is a conformational disease, and one of the most common systemic amyloidosis. It is characterized by the deposition of amyloid aggregates of immunoglobulin light chains in organs and tissues. 6aJL2R24G is a recombinant variant of the λ6a germline protein, a germline present in 25 % of the amyloid-associated λ6a light chain amyloidosis cases. In this study, using spectroscopic and computational methodologies, we found that the interaction of this protein with Zn(II) accelerates amyloid fibril initiation and slows down elongation, without altering the fiber morphology. Also, neither the thermal stability nor the secondary structure are altered by the interaction with the metal ion, as measured by circular dichroism. Isothermal calorimetry titration showed that the protein has two binding sites with affinities in the micromolar range. Molecular dynamics simulations suggest that the interaction between 6aJL2R24G and Zn(II) destabilizes strand A, strand G and the EF loop, making the protein more prone to initiate the formation of amyloid fibers. Furthermore, models of 6aJL2R24G dimers and tetramers with Zn(II) suggest that Zn(II) promotes the association of the proteins, involving histidine, aspartate, and glutamate residues, with multiple different geometries, effectively raising the local protein concentration and promoting seed formation, but adopting conformations different from the one required for further monomer addition to the fiber.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113012"},"PeriodicalIF":3.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosome-targeted theranostics: Integration of real-time fluorescence imaging and controlled drug delivery via Zn(II)-Schiff Base complexes","authors":"Xixi Lai ,&nbsp;Tianxiao Lu ,&nbsp;Fusheng Zhang ,&nbsp;Arshad Khan ,&nbsp;Yili Zhao ,&nbsp;Xin Li ,&nbsp;Shuo Xiang ,&nbsp;Kuailu Lin","doi":"10.1016/j.jinorgbio.2025.113015","DOIUrl":"10.1016/j.jinorgbio.2025.113015","url":null,"abstract":"<div><div>The development of lysosome-targeted theranostic platforms stands at the forefront of precision oncology. However, significant challenges persist in synchronizing real-time diagnostic imaging with spatiotemporal controlled therapeutic delivery. Current systems commonly encounter issues such as suboptimal quantum yields, pH-insensitive release kinetics, and spectral interference between imaging and drug-tracking modes. To address these limitations, we rationally designed a novel series of Zn(II)-Schiff base complexes through coordination chemistry to achieve lysosomal targeting, enhanced optical properties, and microenvironment-responsive drug release. Optical characterization revealed significant red shifts in the absorption and emission spectra after Zn(II) coordination, which can be attributed to the reduction in energy bandgap. Among these complexes, Zn-((2,5-diamino-1,4-benzenedithiol dihydrochloride)-(2,4-Dihydroxybenzaldehyde)) (Zn-MTDH) exhibited the highest quantum yield (63.7 %) and enabled high-contrast lysosomal imaging in 4 T1 breast cancer cells, positioning it as a promising candidate for biological applications. When loaded with camptothecin (CPT), CPT@Zn-MTDH displayed pH-dependent drug release kinetics (81 % cumulative release at pH 5.6 vs. 51 % at pH 7.4 over 36 h). Cellular assays demonstrated that Zn-MTDH exhibits low cytotoxicity and excellent biocompatibility. In contrast, CPT@Zn-MTDH exhibited enhanced cytotoxicity compared to free CPT, highlighting the potential of these complexes for lysosome-targeted cancer therapy. This study establishes Zn(II)-Schiff base complexes as a versatile “track-and-treat” theranostic platform, thereby bridging diagnostic precision with therapeutic efficacy.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113015"},"PeriodicalIF":3.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cluster occupancy- and oxidation state-dependence of Yersinia enterocolitica IscR DNA binding","authors":"Elizabeth Gray,&nbsp;Miaomiao Gao,&nbsp;Justin M. Bradley,&nbsp;Jason C. Crack,&nbsp;Nick E. Le Brun","doi":"10.1016/j.jinorgbio.2025.113011","DOIUrl":"10.1016/j.jinorgbio.2025.113011","url":null,"abstract":"<div><div>Iron‑sulfur (Fe–S) clusters are protein cofactors essential for life. Their assembly requires dedicated cellular machineries, such as the ISC system, found in <em>Escherichia coli</em> and many other bacteria. ISC is regulated by IscR, a member of the Rrf2 family of transcriptional regulators. <em>E. coli</em> IscR (<em>Ec</em>IscR) binds a [2Fe–2S] cluster and, in this form, functions as a repressor of the <em>isc</em> operon. Under aerobic conditions there is an increased cellular demand for Fe–S clusters, and apo IscR accumulates resulting in upregulation of ISC. Currently, the signal that <em>Ec</em>IscR directly responds to is not clear. Little is known about other IscR homologs and whether key functional features of the <em>E. coli</em> protein are broadly shared. Here, we report studies of the IscR homolog from the pathogen <em>Yersinia enterocolitica</em>. <em>Y. enterocolitica</em> IscR (<em>Ye</em>IscR) is ∼80 % identical to <em>Ec</em>IscR and binds a [2Fe–2S] cluster most likely coordinated by three conserved Cys residues and one His. Isolated in the 1+ oxidation state, exposure to O₂ or other oxidants resulted in rapid oxidation of the cluster to the +2 state and slow cluster loss. The cluster was relatively insensitive to iron chelators, indicating that it is not labile. While the trigger for degradation of the <em>Ye</em>IscR cluster to generate the apo form is not clear, loss of the cluster resulted in a ∼10-fold decrease in DNA affinity. The oxidation state of the cluster was found to be important for DNA binding, with a significant reduction in IscR-bound DNA observed upon oxidation, suggesting possible physiological importance.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113011"},"PeriodicalIF":3.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of thiosemicarbazide-based zinc complexes and evaluation of their inhibition of bacterial biofilm formation via targeting extracellular proteins","authors":"Hazrat Bilal ,&nbsp;Cai-Xiang Zhang ,&nbsp;Muhammad Iqbal Choudhary ,&nbsp;Muhammad Raza Shah ,&nbsp;Sukanya Dej-adisai ,&nbsp;Yanghan Liu ,&nbsp;Zhen-Feng Chen","doi":"10.1016/j.jinorgbio.2025.113014","DOIUrl":"10.1016/j.jinorgbio.2025.113014","url":null,"abstract":"<div><div>Three new zinc(II) complexes with N-benzyl-2-((2-hydroxynaphthalen-1-yl)methylene) hydrazine-1-carbothioamide<strong>-</strong>methanol solvate (<strong>L</strong>), 1,10-phenanthroline (phen), and pyridine (py) as ligands, were synthesized and fully characterized. They are named as [Zn₂(L)₂Cl₂)].CH₃OH (<strong>1</strong>), [Zn(L)(phen)].CH₃OH (<strong>2</strong>), and [Zn₂(L)₂(py)₂] (<strong>3</strong>). Complex <strong>1</strong> and <strong>3</strong> are dinuclear structures. Complex <strong>1</strong> contains two <strong>L</strong> ligands; complex <strong>3</strong> also contains two <strong>L</strong> ligands in addition of two py as co-ligands, and complex <strong>2</strong> is mononuclear with one <strong>L</strong> and one phen as co-ligand. The in vitro antibacterial activities of complexes <strong>1</strong>–<strong>3</strong> were tested on five bacterial strains with minimum inhibitory concentrations (MICs) of 1.56 to 64 μg/mL. Complexes <strong>1</strong> and <strong>2</strong> exhibited significantly stronger antibacterial activity against <em>Enterococcus faecalis</em> (<em>E. faecalis</em>) and methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) (<em>S. aureus</em>) than <strong>L</strong>, complex <strong>3</strong>, and Vancomycin. The complexes <strong>1</strong> and <strong>2</strong> inhibited bacterial biofilm formation at concentrations from 0.5 to 10 μg/mL, higher than <strong>L</strong>, complex <strong>3</strong> and Vancomycin. Complexes <strong>1</strong> and <strong>2</strong> strongly interacted with extracellular proteins (ECPs) of bacterial biofilms. Furthermore, molecular docking (MD) studies have validated the interactions of <strong>L</strong> and complexes <strong>1–3</strong> with biofilm-associated proteins (Baps) and <em>SARS-CoV-2</em> receptors, positioning these zinc(II) complexes as promising candidates for developing antibacterial and anti-biofilm agents.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113014"},"PeriodicalIF":3.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monomeric class II chelatase with four histidine residues at the active site, designated Mch4 chelatase, shows evolutionary trails from ancestral to descendant-types","authors":"Shoko Ogawa,&nbsp;Yuuma Oyamada,&nbsp;Hiroumi Saito,&nbsp;Takashi Fujishiro","doi":"10.1016/j.jinorgbio.2025.113010","DOIUrl":"10.1016/j.jinorgbio.2025.113010","url":null,"abstract":"<div><div>Class II chelatases catalyze the insertion of divalent metal ions into tetrapyrroles during the biosynthesis of metal-tetrapyrroles, and are regarded as standard models for investigating chelation mechanisms. The catalytic core of class II chelatases exhibits either a homodimer- or a monomer-type architecture with similar overall folds and different catalytic His residues: four His residues in the homodimer type and one or two His residues in the monomer type. These structural features of the two types of chelatases have led to the hypothesis that the monomer-type is a “descendant” evolved from the homodimer-type “ancestor”. However, there has been no report on naturally-occurring “evolutionary intermediate”-type of chelatases to support this hypothesis. Here, we show the discovery and characterization of such “evolutionary intermediate”-type chelatases. Because this type of chelatases was classified into <u>m</u>onomeric <u>ch</u>elatases with <u>four</u> histidine residues at the active site, we named these chelatases Mch4. Gene complement analysis showed Mch4s could play a role in Fe²⁺ insertion into sirohydrochlorin. Notably, Mch4s did not utilize coproporphyrin III or protoporphyrin IX in vivo assay. In addition, in vitro functional analysis of Mch4s demonstrated that they could utilize Ni²⁺, Co²⁺ as well as Fe²⁺ insertion into sirohydrochlorin. These findings suggest that nickel chelatase activity with sirohydrochlorin was maintained in the hypothetical class II chelatase evolution from homodimeric ancestor-type, to monomeric evolutionary-intermediate-type Mch4, followed by changes in the metal and tetrapyrrole preferences of some descendant chelatases through further evolution, such as further substitution of His at their active sites.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113010"},"PeriodicalIF":3.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ligand esterification on the cytotoxicity against breast cancer cells of ruthenium(II)/dppb pyridinedicarboxylate complexes","authors":"Mariana Santoro de Camargo ,&nbsp;Rone Aparecido De Grandis ,&nbsp;Ayrton Corrêa Galo ,&nbsp;Flávia Aparecida Resende ,&nbsp;Pedro Henrique Salgado Marcon ,&nbsp;Javier Ellena ,&nbsp;João Honorato de Araujo-Neto ,&nbsp;Alzir Azevedo Batista","doi":"10.1016/j.jinorgbio.2025.113008","DOIUrl":"10.1016/j.jinorgbio.2025.113008","url":null,"abstract":"<div><div>Here we report the synthesis and characterization of five new ruthenium(II) complexes with the general formula [Ru(N<img>O)₂(dppb)], where dppb is 1,4-bis(diphenylphosphino)butane and the N<img>O ligands are derivatives of pyridinecarboxylic acids: picolinic acid (<strong>C20</strong>), 2,3- (<strong>C23</strong>), 2,4- (<strong>C24</strong>), and 2,5-pyridinedicarboxylic acids (<strong>C25</strong>), as well as the monoester derivative of 2,4-pyridinedicarboxylic acid (<strong>C24e</strong>), obtained by Fischer esterification. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR spectroscopy (¹H and ³¹P{¹H}), and single-crystal X-ray diffraction (for <strong>C23</strong> and <strong>C24</strong>). The stability of the complexes in solution was confirmed by UV–Vis spectroscopy in DMSO and by ³¹P{¹H} NMR in a DMSO/DMEM mixture (for <strong>C24</strong>), with no evidence of significant speciation reactions. Biological assays revealed that complexes <strong>C20</strong> and <strong>C24e</strong> exhibit significant cytotoxic activity and selectivity against human breast cancer cell lines (MCF-7 and MDA-MB-231) over non-tumorigenic HaCaT cells. Notably, <strong>C20</strong> remained active in three-dimensional spheroid models of MCF-7 cells, showing greater potency than cisplatin. Additionally, both <strong>C20</strong> and <strong>C24e</strong> did not induce mutagenic effects or generate intracellular reactive oxygen species, suggesting alternative mechanisms of cytotoxicity. These findings support the potential of picolinic and esterified pyridinedicarboxylic acid ruthenium(II) complexes as promising antitumor agents.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113008"},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photodynamic activity of Zn(II) phthalocyanines containing polyoxyethylene side chains in malignant melanoma and colorectal cancer cell lines","authors":"Gizem Gümüşgöz Çelik ,&nbsp;Başak Aru ,&nbsp;Mehmet Menaf Ayhan ,&nbsp;Gülderen Yanıkkaya Demirel ,&nbsp;Ayşe Gül Gürek","doi":"10.1016/j.jinorgbio.2025.113007","DOIUrl":"10.1016/j.jinorgbio.2025.113007","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is a treatment modality that activates apoptosis as the preferred pathway of cell death by exposing the target area to light of a wavelength within the spectrum of an administered photosensitizer (PS). Here, we aimed to investigate the anticancer mechanisms of non-peripheral zinc phthalocyanines substituted with either four (np-O-ZnPc1 and np-S-ZnPc1) or eight (np-O-ZnPc2 and np-S-ZnPc2) triethylene monomethyl glycol groups to compare the effects of heteroatoms and substituent number in a systematic manner. Comparison with unsubstituted Zn(II)-phthalocyanine (ZnPc) suggests that substitution of triethylene monomethylglycol with ZnPc tends to increase the singlet oxygen yield while decreasing the fluorescence quantum yield for all compounds. In addition, an increasing fluorescence half-life was observed with the exception of np-O-ZnPc2. The cytotoxicity of the compounds was evaluated on colorectal cancer (HCT116), malignant melanoma (SH-4) and a skin keratinocyte cell line (HaCaT). The optimal incubation time and light dose were determined and the half maximal inhibitory concentrations (IC50) for each cell line were calculated. Programmed cell death pathways, mitochondrial function and protein expression of chemokine receptors were examined. The compounds significantly reduced cell viability and promoted apoptosis in both cancer cell lines. Structurally, compounds with oxygen heteroatoms exhibited higher anticancer activity than those with sulfur atoms. The observation of an increase in CCR7 and CXCR4 proteins as a result of PDT highlights the need for further detailed evaluation of the effects of PDT with the offered phthalocyanines on the invasive and migratory properties of cancer cells.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113007"},"PeriodicalIF":3.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating indole‑gold(I) based complexes as potential anti lymphoma agents by disrupting the thioredoxin reductase/glutathione peroxidase axis","authors":"Sicong Wang ,&nbsp;Min Shan ,&nbsp;Zhongren Xu ,&nbsp;Guizhi Jiang ,&nbsp;Mengshi Wang ,&nbsp;Yanyu Zhou ,&nbsp;Xiao Zhao ,&nbsp;Kathryn F. Tonissen ,&nbsp;Wukun Liu ,&nbsp;Giovanna Di Trapani","doi":"10.1016/j.jinorgbio.2025.113004","DOIUrl":"10.1016/j.jinorgbio.2025.113004","url":null,"abstract":"<div><div>Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, represent promising targets for cancer therapy. Overexpression of these systems has been reported in many cancers, including lymphoma and considered as a mechanism of protection for cancer cells from the high levels of reactive oxygen species (ROS). Over several decades, metal-based complexes including gold complexes such as auranofin have shown anticancer activity by targeting thiols and selenol groups in the active site of thioredoxin reductase (TrxR). However, lack of selectivity, severe side effects or resistance to therapy have been widely reported. Recently, glutathione peroxidase (Gpx) has been reported as one of the key proteins that regulate ferroptosis in cells. To expand the armory for targeting antioxidant systems, in this study eleven new indole-metal complexes were synthesized and assessed for their antiproliferative activity in lymphoma cell lines. The indole‑gold(I)-based complexes showed the best anti-lymphoma activity <em>via</em> inhibiting TrxR and Gpx, but not glutathione reductase (GR), when compared to the indole‑iron-based and cobalt-based complexes. Further investigation revealed that two of the indole‑gold(I)-based complexes, <strong>3h</strong> and <strong>3i</strong>, induced the expression of ferroptosis-related genes and an increase in lipid peroxidation, indicating activation of ferroptosis in these cells. The <em>in vivo</em> study also revealed that these complexes significantly inhibited angiogenesis by reducing formation of blood vessels in zebra fish embryos. Overall, these results show the potential of <strong>3h</strong> and <strong>3i</strong> as TrxR and Gpx inhibitors in lymphoma cells, warranting further assessment as anticancer agents and potential inducers of ferroptosis.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113004"},"PeriodicalIF":3.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iridium(III) complexes as type I photosensitizers for hypoxic two-photon photodynamic therapy","authors":"Zanru Tan ,&nbsp;Jiang Feng ,&nbsp;Zixin Tang ,&nbsp;Tao Feng ,&nbsp;Taihong Liu ,&nbsp;Yukun Zhao ,&nbsp;Hui Chao","doi":"10.1016/j.jinorgbio.2025.113006","DOIUrl":"10.1016/j.jinorgbio.2025.113006","url":null,"abstract":"<div><div>Photodynamic therapy (PDT), a non-invasive therapeutic modality, has significantly improved skin cancer treatment in recent years. Nonetheless, the limitations associated with conventional photosensitizers, such as their substantial dependence on oxygen and restricted light penetration, continue to pose considerable challenges for clinical applications. Herein, five Iridium(III) complexes have been developed as type I photosensitizers for two-photon PDT targeting melanoma. These complexes exhibit notable two-photon absorption (TPA) cross-sections (σ2 ≥ 100 GM) and high yields of reactive oxygen species (ROS) under hypoxic conditions, leading to mitochondrial damage and subsequent apoptosis through ROS generation with low doses of single or two-photon excitation. Notably, <strong>Ir4@PEG</strong> exhibits an IC₅₀ value of 2.1 μM and a phototoxicity index (PI) of 47 under hypoxic conditions. Cellular assays indicate that <strong>Ir4@PEG</strong> initially targets and localizes within lysosomes, where the lysosomal membrane is subsequently compromised upon light stimulation, resulting in <strong>Ir4</strong> transferring and damaging mitochondria, causing cell apoptosis. Additionally, <strong>Ir4@PEG</strong> demonstrates improved tumor penetration, significant ROS production, and marked phototoxicity in hypoxic three-dimensional tumor spheroids. These findings provide new insights into designing oxygen-independent, metal-based two-photon photodynamic therapies against hypoxic melanoma.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113006"},"PeriodicalIF":3.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel platinum(IV) prodrug of cisplatin axially conjugated with cannabidiol induces mitochondrial dysfunction and synergistically enhances anti-tumor effects","authors":"Rong Lv ,&nbsp;Pengmin Shi ,&nbsp;Zhiping Lu ,&nbsp;Tangli Wei ,&nbsp;Jing Yang ,&nbsp;Xiali Liao ,&nbsp;Bo Yang ,&nbsp;Chuanzhu Gao","doi":"10.1016/j.jinorgbio.2025.113003","DOIUrl":"10.1016/j.jinorgbio.2025.113003","url":null,"abstract":"<div><div>Classical cisplatin-based chemotherapeutic drugs are widely used in clinical practice. In recent years, novel platinum-based antitumor drugs have focused on replacing classical cisplatin-like Pt(II) complexes with relatively inert Pt(IV) prodrugs to overcome drug resistance and reduce toxic side effects. Based on the excellent physiological and pharmacological activities of cannabidiol (CBD), this study designed and synthesized novel Pt(IV) prodrugs W1-W6, which are axial conjugates of cisplatin with CBD and specific active small molecules. These prodrugs demonstrated more significant antitumor activity against tested tumor cell lines. Among them, the multifunctional Pt(IV) prodrug W5, conjugated with CBD and the PDK inhibitor DCA, exhibited excellent activity against both platinum-sensitive and cisplatin-resistant tumor strains. The IC₅₀ value of W5 for the A549R tumor strain was 8.53 ± 0.76 μM, significantly higher than that of the cisplatin group and 3.64 times the activity of CBD alone, demonstrating strong synergistic antitumor activity and potential to overcome cisplatin resistance. W5 is reduced by GSH in A549R cells, releasing CBD and Pt(II). Pt(II) binds to DNA, inducing damage and inhibiting repair, while CBD activates pro-apoptotic proteins, leading to mitochondrial dysfunction. Simultaneously, W5 reduces the levels of ROS scavengers, triggering endoplasmic reticulum dysfunction. These three mechanisms synergistically promote tumor cell apoptosis and overcome drug resistance. This design integrates multiple mechanisms through axial functionalization, breaking through the limitation of traditional platinum drugs targeting DNA alone, and achieves synergistic effects by regulating metabolism and intervening in the immune microenvironment.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"272 ","pages":"Article 113003"},"PeriodicalIF":3.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}