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MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2

Xiao Han1,2,3, Yupeng Zhang3, Yin Li3

  • 1Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.

Cell Proliferation
|June 26, 2024
PubMed

Insights

Micheliolide (MCL) overcomes tamoxifen resistance in breast cancer by inhibiting ASAH1 and boosting antioxidant defenses via NRF2/KEAP1. This novel agent shows promise for treating tamoxifen-resistant breast cancer (TAMR-BC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tamoxifen resistance is a significant clinical challenge in breast cancer (BC) treatment.
  • Micheliolide (MCL) is a novel antitumor agent with limited research on its role in BC therapy.
  • Drug-resistant BC cells exhibit high oxidative stress and abnormal activation of Amidohydrolase 1 (ASAH1).

Purpose of the Study:

  • To investigate the role of MCL in overcoming tamoxifen resistance in breast cancer.
  • To elucidate the molecular mechanisms by which MCL affects tamoxifen-resistant BC cells.
  • To evaluate the therapeutic potential of MCL and its prodrug ACT001 in preclinical models.

Main Methods:

  • Utilized tamoxifen-resistant breast cancer cell lines (MCF7TAMR, T47DTAMR).
  • Investigated the effects of MCL on ASAH1 expression, oxidative stress, and cell proliferation.
  • Examined the involvement of AKT and NRF2/KEAP1 pathways in MCL's mechanism of action.
  • Assessed tumor growth inhibition by MCL's prodrug ACT001 in xenograft models.

Main Results:

  • MCL inhibited ASAH1 expression and cell proliferation in tamoxifen-resistant BC cells.
  • MCL counteracted high oxidative stress by activating the NRF2/KEAP1 antioxidant pathway.
  • MCL suppressed the ROS/AKT signaling pathway, reducing ASAH1 activation.
  • ACT001 demonstrated significant tumor growth inhibition in preclinical TAMR-BC models.

Conclusions:

  • ASAH1 plays a critical role in mediating tamoxifen resistance in ER-positive breast cancer.
  • MCL effectively combats tamoxifen resistance by modulating oxidative stress and inhibiting ASAH1.
  • MCL's ability to activate the cellular antioxidant system and target the ROS/AKT pathway makes it a promising therapeutic agent for TAMR-BC.

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