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<p>This work demonstrates the antiferroptotic and cytotoxic effects of 2-aminomethyl phenothiazine (PTZ-NH<sub>2</sub>), and its alkyl derivative (PTZ-capryl) and mitochondria-targeted triphenylphosphonium conjugate (PTZ-TPP) on BT-474 cells, as well as their effects on isolated rat liver mitochondria. It was found that all studied compounds at 0.5 and 1 μM concentrations have a protective effect in the erastin-induced ferroptosis model. This effect of the tested compounds may be associated with the elimination of ROS overproduction in erastin-treated cells. The antioxidant effect of the compounds was also demonstrated on isolated rat liver mitochondria. At the same time, high concentrations of PTZ-NH<sub>2</sub> had a cytotoxic effect on BT-474 cells (IC<sub>50</sub>=55 μM), and it was significantly enhanced in the case of PTZ-TPP (IC<sub>50</sub>=15 μM), which is possibly due to the mitochondrial targeting of PTZ-TPP. In contrast, the alkyl derivative did not exhibit cytotoxic action up to a maximum concentration of 100 μM, which allows it to be recommended as a promising antiferroptotic agent with a wide therapeutic window. The current findings discuss the possible mechanisms of inhibitory action of the tested compounds on ferroptotic cell death.</p>

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2-Aminomethyl phenothiazine, its alkyl and triphenylphosphonium derivatives suppress erastin-induced ferroptosis in BT-474 cells but exhibit distinct cytotoxic activities

  • 期刊论文

  • 发表日期：

    2025年3月5日

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  • Mikhail V. Dubinin,
  • Anna I. Ilzorkina,
  • Darya A. Nedopekina,
  • Natalia V. Mikina,
  • Natalia V. Belosludtseva,
  • Rezeda R. Khalitova,
  • Jun Moni Kalita,
  • Eldar V. Davletshin,
  • Anna Yu. Spivak,
  • Damiki Laloo,
  • Konstantin N. Belosludtsev

摘要

This work demonstrates the antiferroptotic and cytotoxic effects of 2-aminomethyl phenothiazine (PTZ-NH2), and its alkyl derivative (PTZ-capryl) and mitochondria-targeted triphenylphosphonium conjugate (PTZ-TPP) on BT-474 cells, as well as their effects on isolated rat liver mitochondria. It was found that all studied compounds at 0.5 and 1 μM concentrations have a protective effect in the erastin-induced ferroptosis model. This effect of the tested compounds may be associated with the elimination of ROS overproduction in erastin-treated cells. The antioxidant effect of the compounds was also demonstrated on isolated rat liver mitochondria. At the same time, high concentrations of PTZ-NH2 had a cytotoxic effect on BT-474 cells (IC50=55 μM), and it was significantly enhanced in the case of PTZ-TPP (IC50=15 μM), which is possibly due to the mitochondrial targeting of PTZ-TPP. In contrast, the alkyl derivative did not exhibit cytotoxic action up to a maximum concentration of 100 μM, which allows it to be recommended as a promising antiferroptotic agent with a wide therapeutic window. The current findings discuss the possible mechanisms of inhibitory action of the tested compounds on ferroptotic cell death.