Thalidomide-based Pt(IV) prodrugs designed to exert synergistic effect of immunomodulation and chemotherapy.

Abstract

Combination of immune- and chemo-therapy has become a new trend in cancer treatment. Food and Drug Administration (FDA)-approved immune-modulatory agent, thalidomide, can modulate the related proteins of upstream signaling pathway of programmed cell death-ligand 1 (PD-L1), including nuclear transcription factor κB (NF-κB), hypoxia inducible factor-1α (HIF-1α), epidermal growth factor receptor (EGFR), and signal transducer and activator of transcription 3 (STAT3), all acting as key antitumor target proteins. In this work, we conjugated thalidomide with oxidized cisplatin to construct multi-functional Pt(IV) prodrugs, named thaliplatins 4-6, to investigate the anti-tumor effect of immuno- and chemo-therapy. Among them, thaliplatin 6 exerted remarkable cytotoxicity against the tested cancer cell lines, showing 15-26 and 9-20 times higher IC50 values than those of single cisplatin or the combination of cisplatin + thalidomide, respectively. Moreover, thaliplatin 6 could rapidly accumulated into cells, markedly triggered DNA damage, and induced cell S phase arrest and apoptosis, as well as inhibited cell migration and invasion in breast carcinoma cell line (MCF-7). Fluorescent confocal and western blotting experiments proved that 6 significantly regulated NF-κB, EGFR, HIF-1α and phosphor-signal transducer and activator of transcription 3 (p-STAT3), and simultaneously inhibited PD-L1 expression to interrupt programmed cell death 1 (PD-1)/PD-L1 signaling pathway, suggesting a synergistic action of cisplatin and thalidomide. Most strikingly, in vivo tests indicated that 6 effectively decreased tumor growth with no observable systemic toxicity, being superior to the anticancer efficacy of cisplatin.

• Authors: Zhe Li, Xiao-Jing Ding, Xin Qiao, Xiao-Meng Liu, Xin Qiao, Cheng-Zhi Xie, Rui-Ping Liu, Jing-Yuan Xu
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 232 Pg. 111842 (07 2022) ISSN: 1873-3344 [Electronic] United States
• PMID: 35472743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• NF-kappa B
• Prodrugs
• STAT3 Transcription Factor
• Thalidomide
• ErbB Receptors
• Cisplatin

Topics

• B7-H1 Antigen (metabolism)
• Cell Line, Tumor
• Cisplatin
• ErbB Receptors (metabolism)
• Immunomodulation
• NF-kappa B (metabolism)
• Prodrugs (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Thalidomide (pharmacology)