Phenoxazine Derivative ST61 Displays an Oxidative-Stress-Mediated Cytotoxic Activity Against Human Cancer Cells

  • Biomolecules. 2026 May 6;16(5):689. doi: 10.3390/biom16050689.
Adamantia Papadopoulou  1 ,  Socratis Avgeris  2 ,  Savvas Thysiadis  3 ,  Christos Siokatas  3 ,  Stelios Astaras  1 ,  Faye Soukou  1 ,  Eleni Mavrogonatou  1 ,  Harris Pratsinis  1 ,  Gerassimos E Voutsinas  2 ,  Vasiliki Sarli  3 ,  Dimitris Kletsas  1
Affiliations
  • 1. Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", 15341 Athens, Greece.
  • 2. Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", 15341 Athens, Greece.
  • 3. Organic Chemistry Laboratory, School of Chemistry, Faculty of Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
PMID: 42194038 DOI: 10.3390/biom16050689
Abstract

Ninety-five structurally diverse chemically synthesized compounds, retrieved from the chemical library of the national research infrastructure OPENSCREEN-GR, were subjected here to a structure-agnostic bioactivity-driven screen focused on putative anti-cancer activities using a number of human cell lines derived from diverse types of Cancer. Interestingly, the top four compounds that displayed a broad anti-cancer activity (with no apparent photosensitizing activity) during unbiased biological evaluation were then identified as phenoxazine derivatives. In addition to their cytotoxic activity, phenoxazine derivatives BS115 and ST61 were also found to be cytostatic by inducing a p53-independent G2/M cell cycle arrest as well as a G0/G1 arrest only in cells harboring a functional p53. A kinetics analysis using two multiplex immunoassays and siRNA-mediated knockdown of HSP27 revealed that the latter protein is a key molecule in the response of Cancer cells to ST61 via its phosphorylation by p38 MAPK. The main mechanism underlying ST61's anti-cancer activity was found to involve oxidative stress, as scavenging of ST61-induced Reactive Oxygen Species by N-acetyl-cysteine led to the abrogation of the compound's cytotoxic effect.

Keywords
HSP27; MCF7 breast cancer cells; ROS generation; anti-cancer activity; oxidative stress; phenoxazines.
Products