Thermal Proteome Profiling Strategy Identifies CNPY3 as a Cellular Target of Gambogic Acid for Inducing Prostate Cancer Pyroptosis

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(12), С. 10005 - 10011

Опубликована: Март 21, 2024

There is an urgent requirement to acquire a comprehensive comprehension of novel therapeutic targets for prostate cancer facilitate the development medications with innovative mechanisms. In this study, we identified gambogic acid (GBA) as specific pyroptosis inducer in prostatic cells. By using thermal proteome profiling (TPP) strategy, revealed that GBA induces by directly targeting canopy FGF signaling regulator (CNPY3), which was previously considered "undruggable". Moreover, through utilization APEX2-based proximity labeling method, found recruited delactatease SIRT1, resulting elimination lysine lactylation (Kla) on CNPY3. Of note, SIRT1-mediated delactylation influenced cellular localization CNPY3 promote lysosome rupture triggering pyroptosis. Taken together, our study distinctive target induction and its potential application therapy.

Язык: Английский

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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(4), С. 1742 - 1758

Опубликована: Дек. 16, 2023

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to activation cellular oxidative stress and immune responses. While role in promoting inflammation hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which composed oxaliplatin (Oxa) acetaminophen (APAP), enhance anti-tumor amplify response. Our findings demonstrate that OAP2 induces nuclear damage, resulting production DNA. Additionally, downregulates expression Sam50, promote mtDNA secretion, double-stranded accumulation ultimately synergistically activating intracellular cGAS-STING pathway. The induced by overcomes limitations Oxa STING pathway simultaneously promotes gasdermin-D-mediated cell pyroptosis. also dendritic maturation enhances quantity efficacy cytotoxic T cells, thereby inhibiting cancer proliferation metastasis. Briefly, our study introduces first small-molecule inhibitor regulates for active immunotherapy research, may provide creative idea targeting organelle therapy.

Язык: Английский

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Complexes of Ruthenium(II) as Promising Dual-Active Agents against Cancer and Viral Infections

Pharmaceuticals, Год журнала: 2023, Номер 16(12), С. 1729 - 1729

Опубликована: Дек. 15, 2023

Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, ruthenium complexes, are under study possible anticancer antiviral agents. The two Ru(III) Ru(II) namely, BOLD-100 RAPTA-C, presently being studied in a clinical trial preclinical studies evaluation, respectively, Interestingly, has also recently demonstrated activity against SARS-CoV-2, which is virus responsible COVID-19 pandemic. Over last years, much effort dedicated discovering new dual anticancer-antiviral Ru-based complexes could be very suitable respect. Thus, review focuses on most recent regarding newly synthesized use and/or

Язык: Английский

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Developing a Hetero-Trinuclear Erbium(III)–Copper(II) Complex Based on Apoferritin: Targeted Photoacoustic Imaging and Multimodality Therapy of Tumor

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(22), С. 15424 - 15436

Опубликована: Ноя. 13, 2023

For the integration of targeted diagnosis and treatment tumor, we innovatively designed synthesized a single-molecule hetero-multinuclear Er(III)–Cu(II) complex (ErCu2) then constructed an ErCu2@apoferritin (AFt) nanoparticle (NP) delivery system. ErCu2 ErCu2@AFt NPs not only provided evident photoacoustic imaging (PAI) signal tumor but also effectively inhibited growth by integrating photothermal therapy, chemotherapy, immunotherapy. improved targeting ability decreased systemic toxicity in vivo. Furthermore, confirmed that inducing apoptosis autophagy cells activating immune The study provides novel strategy to develop therapeutic metal agents reveals their potential for accurate multimodality therapy cancer.

Язык: Английский

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A novel Au(III) agent designed to inhibit tumor growth and metastasis through inducing immunogenic cell death

Rare Metals, Год журнала: 2024, Номер unknown

Опубликована: Июль 22, 2024

Язык: Английский

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Developing a Palladium(II) Agent to Overcome Multidrug Resistance and Metastasis of Liver Tumor by Targeted Multiacting on Tumor Cell, Inactivating Cancer-Associated Fibroblast and Activating Immune Response

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(18), С. 16296 - 16310

Опубликована: Сен. 5, 2024

To targeted overcome the multidrug resistance (MDR) and metastasis of liver tumors, we proposed to develop a palladium (Pd) agent based on specific residue human serum albumin (HSA) for multiacting tumor cell other components in microenvironment. this end, series Pd(II) 2-acetylpyridine thiosemicarbazone compounds were optimized obtain compound (5b) with significant cytotoxicity against HepG2/ADM cells. Subsequently, constructed HSA-5b complex delivery system revealed structural mechanism HSA delivering 5b. Importantly, 5b/HSA-5b effectively inhibited growth resistant enhanced targeting ability 5b reduced its side effects

Язык: Английский

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Developing a Rhodium(III) Complex to Reprogram the Tumor Immune and Metabolic Microenvironments: Overcoming Multidrug Resistance and Metastasis in Non-Small Cell Lung Cancer

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(19), С. 17243 - 17258

Опубликована: Сен. 19, 2024

To effectively inhibit the growth and metastasis of non-small cell lung cancer (NSCLC) overcome its multidrug resistance (MDR), we designed synthesized a series rhodium (Rh, III) 2-benzoylpyridine thiosemicarbazone complexes. Through studying their structure-activity relationships, identified Rh(III) complex (Rh4) with excellent cytotoxicity against multidrug-resistant cells (A549/ADR cells). Additionally, successfully constructed an apoferritin (AFt) nanoparticle (NP) delivery system (AFt-Rh4 NPs). Importantly, AFt-Rh4 NPs not only exhibited antitumor antimetastatic capabilities NSCLC

Язык: Английский

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Recent advances in ruthenium（III） complex-loaded nanomaterial for enhanced cancer therapy efficacy

Drug Development and Industrial Pharmacy, Год журнала: 2025, Номер unknown, С. 1 - 18

Опубликована: Янв. 21, 2025

Objective Amid the escalating global cancer incidence, development of effective and safe anticancer drugs is a critical priority in medical research. Addressing clinical shortcomings ruthenium-based are currently prominent focus

Язык: Английский

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Cyclometalated iridium(III)-lonidamine conjugates: Mitochondrial targeting and pyroptosis induction

Journal of Inorganic Biochemistry, Год журнала: 2025, Номер 266, С. 112852 - 112852

Опубликована: Фев. 9, 2025

Язык: Английский

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Design, Synthesis and Bioactive Evaluation of Topo I/c-MYC Dual Inhibitors to Inhibit Oral Cancer via Regulating the PI3K/AKT/NF-κB Signaling Pathway

Molecules, Год журнала: 2025, Номер 30(4), С. 894 - 894

Опубликована: Фев. 14, 2025

The significantly rising incidence of oral cancer worldwide urgently requires the identification novel, effective molecular targets to inhibit progression malignancy. DNA topoisomerase I (Topo I) is a well-established target for treatment, and many studies have shown that different cell genes could be targeted more selectively with one type Topo inhibitor. In this report, new scaffold pyridothieno[3,2-c]isoquinoline 11,11-dioxide was designed via combination key fragment or bioisoster inhibitor azaindenoisoquinolines G-quadruplex binder quindoline. Thirty-two derivatives were synthesized, among which compounds 7be, potent inhibition, exhibited antiproliferative activity against Cal27, lines highly expressing protein. Further indicated 7be also activation PI3K/AKT/NF-κB pathway downregulate level c-MYC, repress colony formation migration Cal27 cells trigger apoptosis autophagy. Molecular docking interact complex mode similar indenoisoquinolines. results xenograft model confirmed promising anticancer efficacy in vivo, tumor growth inhibition (TGI) 64.7% at 20 mg/kg.

Язык: Английский

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