In Vitro and In Vivo Effect of Palladacycles: Targeting A2780 Ovarian Carcinoma Cells and Modulation of Angiogenesis

Inorg Chem. 2021 Mar 15;60(6):3939-3951. doi: 10.1021/acs.inorgchem.0c03763. Epub 2021 Mar 3.

Abstract

Palladacycles are versatile organometallic compounds that show potential for therapeutic use. Here are described the synthesis and characterization of mono- and dinuclear palladacycles bearing diphosphines. Their biological effect was investigated in A2780, an ovarian-derived cancer line, and in normal dermal fibroblasts. The compounds displayed selective cytotoxicity toward the A2780 cell line. Compound 3 decreased the cell viability through cell cycle retention in G0/G1, triggered apoptosis through the intrinsic pathway, and induced autophagy in A2780 cells. Compound 9 also induced cell cycle retention, apoptosis, and cellular detachment. Notably, compound 9 induced the production of intracellular reactive oxygen species (ROS). Our work demonstrated that compound 3 enters A2780 cells via active transport, which requires energy, while compound 9 enters A2780 cells mostly passively. The potential effect of palladacycles in angiogenesis was investigated for the first time in an in vivo chorioallantoic membrane model, showing that while compound 3 displayed an antiangiogenic effect crucial to fighting cancer progression, compound 9 promoted angiogenesis. These results show that palladacycles may be used in different clinical applications where pro- or antiangiogenic effects may be desirable.

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chickens
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology*
  • Embryo, Nonmammalian / drug effects
  • Female
  • Fibroblasts / drug effects
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / pharmacology*
  • Ovarian Neoplasms / drug therapy
  • Palladium / chemistry
  • Reactive Oxygen Species / metabolism

Substances

  • Angiogenesis Inhibitors
  • Coordination Complexes
  • Organometallic Compounds
  • Reactive Oxygen Species
  • Palladium