Mitochondria-targeted Pt(IV) prodrugs conjugated with an aggregation-induced emission luminogen against breast cancer cells by dual modulation of apoptosis and autophagy inhibition

J Inorg Biochem. 2022 Jan:226:111653. doi: 10.1016/j.jinorgbio.2021.111653. Epub 2021 Oct 27.

Abstract

Theranostic anticancer agents with dual functions of diagnosis and therapy are in highly demand for breast cancer. Herein, a triphenylphosphonium (TPP)-decorated aggregation-induced emission (AIE)-based Pt(IV) prodrug ACPt was developed, which exhibited superior anticancer performance with novel anticancer mechanism of dual modulation of apoptosis and autophagy inhibition. The experimental data showed that ACPt induced increased reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP). The morphology and function of mitochondria were also severely damaged and ACPt showed strong inhibition to both mitochondrial and glycolytic bioenergetics. Moreover, DNA damage and cell cycle arrest in the S-phase were also observed after the ACPt treatment, eventually leading to the apoptosis and autophagy inhibition of cancer cells. Furthermore, ACPt also indicated excellent anti-proliferation activity in 3D multicellular tumor spheroids (MCTSs), suggesting the potential to inhibit solid tumors in vivo. Our observation demonstrated that ACPt could serve as a promising anticancer theranostic agent toward breast cancers for prodrug activation monitoring and image-guided chemotherapy.

Keywords: Anticancer; Apoptosis; Autophagy flux blockage; Mitochondria-targeting; Pt(IV) prodrug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Coordination Complexes* / chemistry
  • Coordination Complexes* / pharmacokinetics
  • Coordination Complexes* / pharmacology
  • Drug Delivery Systems*
  • Female
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / metabolism*
  • Platinum* / chemistry
  • Platinum* / pharmacokinetics
  • Platinum* / pharmacology
  • Prodrugs* / chemistry
  • Prodrugs* / pharmacokinetics
  • Prodrugs* / pharmacology

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Prodrugs
  • Platinum