Targeting ROS-AMPK pathway by multiaction Platinum(IV) prodrugs containing hypolipidemic drug bezafibrate

Abstract

Alterations in lipid metabolism, commonly disregarded in the past, have been accepted as a hallmark for cancer. Exploring cancer therapeutics that interrupt the lipid metabolic pathways by monotherapy or combination with conventional chemotherapy or immunotherapy is of great importance. Here we modified cisplatin with an FDA-approved hypolipidemic drug, bezafibrate (BEZ), via the well-established Pt(IV) strategy, affording two multi-functional Pt(IV) anticancer agents cis,cis,trans-[Pt(NH₃)₂Cl₂(BEZ)(OH)] (CB) and cis,cis,trans-[Pt(NH₃)₂Cl₂(BEZ)₂] (CP) (BEZ = bezafibrate). The Pt(IV) prodrug CB exhibited an enhanced anticancer activity up to 187-fold greater than the clinical anticancer drug cisplatin. Both CB and CP had less toxicity to normal cells, showing higher efficacies and superior therapeutic indexes than cisplatin. Mechanism studies revealed that the bezafibrate-conjugated Pt(IV) complex CB, as a representative, could massively accumulate in A549 cells and genomic DNA, induce DNA damage, elevate intracellular ROS levels, perturb mitochondrial transmembrane potentials, activate the cellular metabolic sensor AMPK, and result in profound proliferation inhibition and apoptosis. Further cellular data also provided evidence that phosphorylation of AMPK, as a metabolic sensor, could suppress the downstream HMGB1, NF-κB, and VEGFA, which may contribute to the inhibition of angiogenesis and metastasis. Our study suggests that the antitumor action of CB and CP mechanistically distinct from the conventional platinum drugs and that functionalizing platinum-based agents with lipid-modulating agents may represent a novel practical strategy for cancer treatment.

Keywords: Apoptosis; Bezafibrate; Hypolipidemic drug; Oxidative stress; Pt(IV) prodrugs; ROS-AMPK pathway.