Metallodrugs in the battle against non-small cell lung cancer: unlocking the potential for improved therapeutic outcomes

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide. Platinum-based chemotherapy is standard-of-care but has limitations including toxicity and resistance. Metal complexes of gold, ruthenium, and other metals have emerged as promising alternatives. This review provides a comprehensive analysis of metallodrugs for NSCLC. Bibliometric analysis reveals growing interest in elucidating mechanisms, developing targeted therapies, and synergistic combinations. Classification of metallodrugs highlights platinum, gold, and ruthenium compounds, as well as emerging metals. Diverse mechanisms include DNA damage, redox modulation, and immunomodulation. Preclinical studies demonstrate cytotoxicity and antitumor effects in vitro and in vivo, providing proof-of-concept. Clinical trials indicate platinums have utility but resistance remains problematic. Non-platinum metallodrugs exhibit favorable safety but modest single agent efficacy to date. Drug delivery approaches like nanoparticles show potential to enhance therapeutic index. Future directions include optimization of metal-based complexes, elucidation of resistance mechanisms, biomarker development, and combination therapies to fully realize the promise of metallodrugs for NSCLC.

Exploring the coordination chemistry of ruthenium complexes with lysozymes: structural and in-solution studies

“…The mechanism of action of NAMI-A-type ruthenium complexes is still not completely understood, and their anticancer properties, in contrast to platinum-based complexes targeting DNA, seem to be tuned by the formation of adducts with proteins. It is commonly believed that the interaction of ruthenium complexes with proteins plays a crucial role in the complexes’ toxicity, biodistribution, bioavailability, and mechanism of action ( Anthony et al, 2020 ; Frei et al, 2020 ; Xu et al, 2023 ). X-ray crystallographic studies provided evidence that NAMI-A ( Chiniadis et al, 2021 ), as well as its analog (AziRu) with a pyridine ligand instead of imidazole, forms adducts with model proteins ( Casini et al, 2010 ; Vergara et al, 2013b ; Messori and Merlino, 2014 ).…”

“…Currently, scientists are increasingly focused on gaining a more detailed understanding of how metallodrugs interact with proteins at the molecular level, as this knowledge is crucial in defining the pharmacological functions of these drugs ( Anthony et al, 2020 ; Frei et al, 2020 ; Xu et al, 2023 ). The formation of adducts between ruthenium and proteins, for instance, can modify the catalytic efficiency of various enzymes ( Bergamo and Sava, 2007 ).…”

Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential

“…Consequently, with the emergence of many biomedical applications of other transition metal complexes, including anticancer and antimicrobial agents, attention is shifting beyond platinum-based compounds [ 1 , 8 , 9 , 10 , 11 ]. The preclinical studies provide evidence that non-platinum agents have the potential to circumvent the problem of chemoresistance and the toxicity of platinum-based agents by exhibiting different specific modes of action, reduced undesirable effects and the ability to overcome drug-resistance mechanisms [ 10 , 12 , 13 ].…”