4.7 Article

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

Journal

EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 939, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.ejphar.2022.175470

Keywords

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

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Mitochondria in tumor cells are different from normal cells and can be targeted for new anticancer agents. The aryl-ureido fatty acid CTU is a prototype of mitochondrion-targeted agents that kill cancer cells by increasing ROS production, activating ER-stress, and promoting apoptosis. However, high doses of CTU are required for in vivo anti-tumor activity, so new strategies are needed to enhance its effectiveness. In this study, a novel aryl-urea called 3-thiaCTU was developed and found to be more active than CTU in promoting cancer cell killing mechanisms in vitro and in mice carrying tumor xenografts. These findings suggest that 3-thiaCTU could be a promising candidate for development as a novel anticancer agent.
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 CTU in vivo in mice that carried MDA-MB-231 cell xenografts. Compared to CTU, 3-thiaCTU pre-vented 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.

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