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Bufalin Induces Programmed Necroptosis in Triple-Negative Breast Cancer Drug-Resistant Cell Lines through

Xiao-Dan Liu1, Cheng-Yang Song2, Cui-Cui Kong3

  • 1Department of Breast Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.

Chinese Journal of Integrative Medicine
|November 26, 2021
PubMed
Abstract

Insights

Bufalin effectively kills triple-negative breast cancer (TNBC) cells, including drug-resistant types, by inducing necroptosis. This occurs through a RIPK1 and reactive oxygen species (ROS) pathway, offering a new strategy for TNBC treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) presents significant treatment challenges due to drug resistance.
  • Developing novel therapeutic strategies to overcome resistance in TNBC is crucial.

Purpose of the Study:

  • To investigate the efficacy and mechanism of bufalin in TNBC drug-resistant cell lines.
  • To elucidate the cell death pathways induced by bufalin in resistant TNBC models.

Main Methods:

  • Utilized TNBC and drug-resistant cell lines (adriamycin- and docetaxel-resistant).
  • Treated cells with varying bufalin concentrations and time points.
  • Assessed cell death patterns using propidium iodide staining, AV-FITC/PI, Hoechst 33342/PI staining, and transmission electron microscopy (TEM).
  • Measured expressions of key proteins (TNF-α, RIPK1, c-caspase 3) and reactive oxygen species (ROS) levels.
  • Investigated the role of RIPK1 and ROS using inhibitors (NEC-1, z-VAD-fmk, N-acetyl cysteine).

Main Results:

  • Bufalin demonstrated dose- and time-dependent cytotoxicity against TNBC and resistant cell lines (P<0.01).
  • Necroptosis emerged as the primary cell death mechanism in resistant cells after 48h bufalin treatment, alongside initial apoptosis.
  • Bufalin treatment upregulated TNF-α pathway components and RIPK1, with necroptosis being inhibitable by NEC-1 and z-VAD-fmk.
  • Increased intracellular ROS levels were observed, and their inhibition by N-acetyl cysteine or NEC-1 attenuated bufalin's killing effect.

Conclusions:

  • Bufalin induces necroptosis in drug-resistant TNBC cells via a RIPK1 and ROS-mediated pathway.
  • This mechanism provides a potential therapeutic avenue for overcoming TNBC drug resistance.
  • Findings support bufalin as a promising agent for clinical application in treating resistant TNBC.
Keywords:
bufalindrug resistantnecroptosisreactive oxygen species pathwaytriple-negative breast cancer

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