Development of Platinum Complexes for Tumor Chemoimmunotherapy

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(10)

Published: Jan. 3, 2024

Abstract Platinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the activity of platinum is not limited to chemical killing effects, but also extends immunomodulatory actions. This review introduced general concept chemoimmunotherapy and summarized progress as chemoimmunotherapeutic agents recent years. developed into inducers immunogenic cell death, blockers immune checkpoint, regulators signaling pathway, modulators microenvironment, etc. The synergy between chemotherapeutic effects reinforces complexes, helps them circumvent drug resistance systemic toxicity. exploration for may create new opportunities revive discovery metal anticancer drugs.

Language: Английский

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Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6218 - 6237

Published: April 4, 2024

Although cisplatin has been widely used for clinical purposes, its application is limited due to obvious side effects. To mitigate the defects of cisplatin, here, six "multitarget prodrugs" were synthesized by linking and NF-κB inhibitors. Notably, complex 9 demonstrated a 63-fold enhancement in activity against A549/CDDP cells with lower toxicity toward normal LO2 compared cisplatin. Additionally, could effectively cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, cell apoptosis through pathway ER stress. Remarkably, inhibited NF-κB/MAPK signaling disrupted PI3K/AKT transduction. Importantly, showed superior vivo antitumor efficiency or combination cisplatin/4, without systemic A549 xenograft models. Our results that dual-acting mechanism endowed complexes high low toxicity, which may represent an efficient strategy cancer therapy.

Language: Английский

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Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 8020 - 8042

Published: May 10, 2024

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking agents glycyrrhetinic acid (GA) were designed synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin than simultaneously displayed good liver-targeting ability. Moreover, can significantly cause DNA damage mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, eventually induce apoptosis. Additionally, effectively inhibit cell migration invasion trigger autophagy ferroptosis HepG-2 cells. More importantly, demonstrated stronger tumor inhibition ability or the combo of cisplatin/GA with almost no systemic toxicity A549 xenograft models. Collectively, could be developed as a potential anti-HCC agent treatment.

Language: Английский

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Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition

Journal of Inorganic Biochemistry, Journal Year: 2023, Volume and Issue: 251, P. 112427 - 112427

Published: Nov. 14, 2023

Language: Английский

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Macromolecules incorporating transition metals in the treatment and detection of cancer and infectious diseases: Progress over the last decade

Coordination Chemistry Reviews, Journal Year: 2024, Volume and Issue: 510, P. 215732 - 215732

Published: March 28, 2024

Language: Английский

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Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to failure of therapy. Here, series ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling TME through suppressing JAK2/STAT3 signaling was developed. A candidate screened out, which displayed potent antiproliferative antimetastatic performance both

Language: Английский

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Design, Synthesis and Evaluation of Diarylidenyl Piperidone-Ligated Platinum (IV) Complexes as Chemoimmunotherapeutic Agents

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117338 - 117338

Published: Jan. 1, 2025

Language: Английский

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Platinum(IV) Complexes Trigger Death Receptors and Natural Killer Cells to Suppress Breast Cancer

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Chemoimmunotherapy is an alternative treatment against cancers. Platinum(IV) complexes FMP and DFMP, coupling formononetin derivative as axial ligand(s), were designed to suppress triple-negative breast cancer (TNBC) by activating death receptors (DRs) natural killer (NK) cells. These show great potential overcome the resistance of TNBC chemotherapy inducing both intrinsic extrinsic apoptosis in Particularly, with one not only induced caspase-3-dependent but also upregulated expression DRs caspase-8, triggered apoptosis, enhanced cytotoxic ability NK92 Moreover, increased release granzyme B, restrained proliferation differentiation myeloid-derived suppressor cells, secretion IL-10, thus inhibiting vitro vivo. The results demonstrate that overcomes chemoresistance immune escape through a new mechanism involving synergy immunotherapy.

Language: Английский

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Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Acquired resistance in cancer remains a significant challenge oncology, posing obstacles to the efficacy of diverse therapeutic approaches. The nuclear factor-kappa B (NF-κB) signaling pathway plays an important role development drug tumor cells. Herein, we employed NF-κB inhibitors and cisplatin synthesize multitarget Pt(IV) antitumor prodrugs. Among them, antiproliferation activity complex 8 demonstrated remarkable 146.92-time increase compared against A549/CDDP Moreover, could effectively induce DNA damage, promote ROS generation, autophagy, trigger mitochondrial apoptosis pathway, suppress cell proliferation through pathway. Furthermore, downregulated levels VEGF HIF-1α exerted antiproliferative PI3K/AKT STAT-3 Interestingly, showed superior vivo than cisplatin, 5a, or their combination, suggesting its potential as promising candidate for further lung treatment.

Language: Английский

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Photoinduced Synergism of Ferroptosis/Pyroptosis/Oncosis by an O₂-Independent Photocatalyst for Enhanced Tumor Immunotherapy

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Due to O2 dependence, hypoxia-induced apoptosis resistance, and immunosuppressive microenvironment, the effect of traditional photodynamic therapy toward hypoxic solid tumors is severely limited. Herein, we report an O2-independent photocatalyst (EBSe) for tumor immunotherapy potentiation via synergism near-infrared (NIR) light-induced ferroptosis/pyroptosis/oncosis. Simple Se ethyl modifications on methylene blue (MB) endow EBSe with a remarkable phototoxicity enhancement (>2500 folds) excellent index (PI > 32,000) 4T1 cells under hypoxia. exhibits self-adaptive processes that generate enhanced type I/II ROS normoxia elevate carbon radical production Interestingly, shows much higher cell uptake undergoes photoinduced lysosomal-to-nucleus translocation, which activates ferroptosis, pyroptosis, oncosis. The three nonapoptotic pathways potentiates antitumor immune responses in tumor-bearing mice. This work offers reliable strategy developing powerful PSs overcome resistance microenvironment tumors.

Language: Английский

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