Frontiers in Bioscience-Landmark (Apr 2024)

A New Indole Derivative, LWX-473, Overcomes Glucocorticoid Resistance in Jurkat Cells by Activating Mediators of Apoptosis

  • Jingrui Song,
  • Kun Yang,
  • Babu Gajendran,
  • Krishnapriya M. Varier,
  • Wenxue Li,
  • Qin Liu,
  • Qing Rao,
  • Yubing Hang,
  • Xiangchun Shen,
  • Sheng Liu,
  • Lei Huang,
  • Mei Xu,
  • Yanmei Li

DOI
https://doi.org/10.31083/j.fbl2904163
Journal volume & issue
Vol. 29, no. 4
p. 163

Abstract

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Background: Glucocorticoids (GCs) are commonly used as the primary chemotherapy for lymphoid malignancies, including acute lymphoblastic leukemia (ALL). However, the development of GC resistance limits their prolonged use. Methods: In this study, we investigated the potential of a newly synthesized indole derivative called LWX-473, in combination with the classic GC Dexamethasone (DEX), to enhance the responsiveness of Jurkat cells to GC treatment. Results: Our findings demonstrate that LWX-473 alone or in combination with DEX significantly improves GC-induced cell apoptosis and arrests the cell cycle in the G1 phase. Notably, the combination of LWX-473 and DEX exhibits superior efficacy in killing Jurkat cells compared to LWX-473 alone. Importantly, this compound demonstrates reduced toxicity towards normal cells. Conclusions: Our study reveals that LWX-473 has the ability to restore the sensitivity of Jurkat cells to DEX by modulating the mitochondrial membrane potential, activating the expression of DEX-liganded glucocorticoid receptor (GR), and inhibiting key molecules in the JAK/STAT signaling pathway. These findings suggest that LWX-473 could be a potential therapeutic agent for overcoming GC resistance in lymphoid malignancies.

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