Designing mitophagy-targeted robustine- and 4-acridinol-rhodium(iii) coordination compounds to overcome cisplatin resistance in A549/DDP lung cancer cells

Abstract

This study aimed to develop a potential theranostic metal-containing drug for overcoming cisplatin (cisPt)-based resistance in A549/DDP lung cancer cells. To achieve this, we proposed the design and synthesis of two rhodium(III) coordination compounds—[Rh(TPP)(Acr)₂Cl] (AcRh) and [Rh(TPP)(Rob)₂]Cl·3CH₃OH (RoRh·3MeOH)—by modifying 4-acridinol (H-Acr), robustine (H-Rob), and the structure of tris(triphenylphosphine)rhodium(I) chloride [(TPP)₃RhCl] dimers. The structure–activity relationships of the compounds were evaluated. RoRh demonstrated remarkable cytotoxicity against the cisPt-resistant A549/DDP (A549cisPt) cells. Moreover, the antitumor mechanism of RoRh is stronger than that of AcRh, as it directly kills cisPt–resistant A549cisPt lung cancer cells by inducing apoptosis and activating the mitophagy pathway. This study describes a promising Rh(III) antitumor agent with H-Rob that can target the mitophagy pathway and address cisPt resistance in lung cancer cells.