Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids

Eur J Pharmacol. 2023 Jan 15:939:175470. doi: 10.1016/j.ejphar.2022.175470. Epub 2022 Dec 18.

Abstract

Mitochondria in tumor cells are functionally different from those in normal cells and could be targeted to develop new anticancer agents. We showed recently that the aryl-ureido fatty acid CTU is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells by increasing the production of reactive oxygen species (ROS), activating endoplasmic reticulum (ER)-stress and promoting apoptosis. However, prolonged treatment with high doses of CTU were required for in vivo anti-tumor activity. Thus, new strategies are now required to produce agents that have enhanced anticancer activity over CTU. In the present study we prepared a novel aryl-urea termed 3-thiaCTU, that contained an in-chain sulfur heteroatom, for evaluation in tumor cell lines and in mice carrying tumor xenografts. The principal finding to emerge was that 3-thiaCTU was several-fold more active than CTU in the activation of aryl-urea mechanisms that promoted cancer cell killing. Thus, in in vitro studies 3-thiaCTU disrupted the mitochondrial membrane potential, increased ROS production, activated ER-stress and promoted tumor cell apoptosis more effectively than CTU. 3-ThiaCTU was also significantly more active than CTUin vivo in mice that carried MDA-MB-231 cell xenografts. Compared to CTU, 3-thiaCTU prevented tumor growth more effectively and at much lower doses. These findings indicate that, in comparison to CTU, 3-thiaCTU is an aryl-urea with markedly enhanced activity that could now be suitable for development as a novel anticancer agent.

Keywords: Endoplasmic reticulum stress; Mitochondria; Pro-apoptotic agents; Reactive oxygen species; Ureido-fatty acids.

MeSH terms

  • Animals
  • Antineoplastic Agents* / metabolism
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress
  • Fatty Acids* / metabolism
  • Fatty Acids* / pharmacology
  • Humans
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria
  • Reactive Oxygen Species / metabolism
  • Urea / pharmacology
  • Urea / therapeutic use

Substances

  • Fatty Acids
  • Urea
  • Reactive Oxygen Species
  • Antineoplastic Agents