Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

Zhang, Ming; Chen, Yan; Liu, Zhifang; Liu, Min; Wang, Qingpeng

doi:10.1021/acs.jmedchem.3c01845

“…In view of these stimulating facts and as a continuation of our interest in developing novel antitumor agents, − it was of great interest for us to design novel platinum(IV) conjugates with EMT suppressing and immunoregulating properties. Isoquinoline alkaloids are an important group of natural bioactive products, which display a wide variety of pharmacological properties such as antimicrobial, antibacterial, antifungal, antitumor, etc. − Canadine (CND) as a unique isoquinoline alkaloid shows much potential as antiproliferative and antimetastasis agents. − The mechanism detection revealed that CND was potent in inhibiting the EMT process, , inhibiting inflammation, and further modulating immune responses. , Accordingly, we intended to incorporate CND into the platinum(IV) system as a functional ligand with the aim of discovering novel platinum(IV) agents with potent antiproliferative and antimetastatic properties.…”

Section: Introductionmentioning

confidence: 99%

Canadine Platinum(IV) Complexes Targeting Epithelial–Mesenchymal Transition as Antiproliferative and Antimetastatic Agents

Chen,

Zhang,

He

et al. 2024

J. Med. Chem.

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Epithelial−mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/β-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3 + and CD8 + T lymphocytes and the macrophage polarization from M2-toward M1-type simultaneously in tumors.

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Platinum‐Metformin Conjugates Acting as Promising PD‐L1 Inhibitors through the AMP‐Activated Protein Kinase Mediated Lysosomal Degradation Pathway

Liu,

Liang,

Cao

et al. 2024

Angewandte Chemie

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With the development of metalloimmunology, the potential of platinum drugs in cancer immunotherapy has attracted extensive attention. Although immunochemotherapy combining PD‐1/PD‐L1 antibodies with platinum drugs has achieved great success in the clinic, combination therapy commonly brings new problems. Herein, we have developed a platinum‐metformin conjugate as a promising alternative to antibody‐based PD‐L1 inhibitors, not only disrupting PD‐1/PD‐L1 axis on cell surface but also down‐regulating the total PD‐L1 levels in non‐small cell lung cancer (NSCLC) cells comprehensively, thus achieving highly efficient immunochemotherapy by a single small molecule. Mechanism studies demonstrate that Pt‐metformin conjugate can selectively accumulate in lysosomes, promote lysosomal‐dependent PD‐L1 degradation via the AMPK‐TFEB pathway, and modulate the upstream regulatory proteins related to PD‐L1 expression (e.g. HIF‐1α and NF‐κB), eventually decreasing the total abundance of PD‐L1 in NSCLC, overcoming tumor hypoxia, and activating anti‐tumor immunity in vivo. This work suggests an AMPK‐mediated lysosomal degradation pathway of PD‐L1 for the first time and provides a unique design perspective for the development of novel platinum drugs for immunochemotherapy.

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Platinum‐Metformin Conjugates Acting as Promising PD‐L1 Inhibitors through the AMP‐Activated Protein Kinase Mediated Lysosomal Degradation Pathway

Liu,

Liang,

Cao

et al. 2024

Angew Chem Int Ed

0

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With the development of metalloimmunology, the potential of platinum drugs in cancer immunotherapy has attracted extensive attention. Although immunochemotherapy combining PD‐1/PD‐L1 antibodies with platinum drugs has achieved great success in the clinic, combination therapy commonly brings new problems. Herein, we have developed a platinum‐metformin conjugate as a promising alternative to antibody‐based PD‐L1 inhibitors, not only disrupting PD‐1/PD‐L1 axis on cell surface but also down‐regulating the total PD‐L1 levels in non‐small cell lung cancer (NSCLC) cells comprehensively, thus achieving highly efficient immunochemotherapy by a single small molecule. Mechanism studies demonstrate that Pt‐metformin conjugate can selectively accumulate in lysosomes, promote lysosomal‐dependent PD‐L1 degradation via the AMPK‐TFEB pathway, and modulate the upstream regulatory proteins related to PD‐L1 expression (e.g. HIF‐1α and NF‐κB), eventually decreasing the total abundance of PD‐L1 in NSCLC, overcoming tumor hypoxia, and activating anti‐tumor immunity in vivo. This work suggests an AMPK‐mediated lysosomal degradation pathway of PD‐L1 for the first time and provides a unique design perspective for the development of novel platinum drugs for immunochemotherapy.

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Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial–Mesenchymal Transition and Arousing Immune Response

Cited by 11 publications

References 47 publications

Canadine Platinum(IV) Complexes Targeting Epithelial–Mesenchymal Transition as Antiproliferative and Antimetastatic Agents

Canadine Platinum(IV) Complexes Targeting Epithelial–Mesenchymal Transition as Antiproliferative and Antimetastatic Agents

Platinum‐Metformin Conjugates Acting as Promising PD‐L1 Inhibitors through the AMP‐Activated Protein Kinase Mediated Lysosomal Degradation Pathway

Platinum‐Metformin Conjugates Acting as Promising PD‐L1 Inhibitors through the AMP‐Activated Protein Kinase Mediated Lysosomal Degradation Pathway

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