A novel heteroleptic Cu(II)-phenanthroline-UDCA complex as lipoxygenase inhibitor and ER-stress inducer in cancer cell lines

J Inorg Biochem. 2023 Sep:246:112301. doi: 10.1016/j.jinorgbio.2023.112301. Epub 2023 Jun 22.

Abstract

A new heteroleptic copper(II) compound named C0-UDCA was prepared by reaction of [Cu(phen)2(OH2)](ClO4)2 (C0) with the bile ursodeoxycholic acid (UDCA). The resulting compound is able to inhibit the lipoxygenase enzyme showing more efficacy than the precursors C0 and UDCA. Molecular docking simulations clarified the interactions with the enzyme as due to allosteric modulation. The new complex shows antitumoral effect on ovarian (SKOV-3) and pancreatic (PANC-1) cancer cells at the Endoplasmic Reticulum (ER) level by activating the Unfolded Protein Response. In particular, the chaperone BiP, the pro-apoptotic protein CHOP and the transcription factor ATF6 are upregulated in the presence of C0-UDCA. The combination of Intact Cell MALDI-MS and statistical analysis have allowed us to discriminate between untreated and treated cells based on their mass spectrometry fingerprints.

Keywords: Copper complex; ER stress; Lipoxygenase; Mass spectrometry; Molecular docking; Solution equilibria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line
  • Copper / chemistry
  • Copper / pharmacology
  • Endoplasmic Reticulum Stress
  • Enzyme Inhibitors / pharmacology
  • Lipoxygenase Inhibitors* / pharmacology
  • Molecular Docking Simulation
  • Neoplasms*
  • Pancreatic Neoplasms
  • Phenanthrolines / chemistry
  • Ursodeoxycholic Acid / pharmacology

Substances

  • Lipoxygenase Inhibitors
  • Ursodeoxycholic Acid
  • Phenanthrolines
  • Copper
  • Enzyme Inhibitors