Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway

Yinhui Dong, Shutao Yin, Jinghua Li, Cheng Jiang, Min Ye, Hongbo Hu

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone-associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL.

Original languageEnglish (US)
Pages (from-to)394-403
Number of pages10
JournalApoptosis
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2011

Fingerprint

Cells
Apoptosis
Breast Neoplasms
Bufanolides
Chemical activation
STAT3 Transcription Factor
Death Domain Receptors
Apoptosis Regulatory Proteins
Down-Regulation
Fluorescein-5-isothiocyanate
Annexin A5
Caspases
Histones
Medicine
Toxicity
Chinese Traditional Medicine
Ligands
Membranes
Permeability
DNA

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Dong, Yinhui ; Yin, Shutao ; Li, Jinghua ; Jiang, Cheng ; Ye, Min ; Hu, Hongbo. / Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway. In: Apoptosis. 2011 ; Vol. 16, No. 4. pp. 394-403.
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Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway. / Dong, Yinhui; Yin, Shutao; Li, Jinghua; Jiang, Cheng; Ye, Min; Hu, Hongbo.

In: Apoptosis, Vol. 16, No. 4, 01.04.2011, p. 394-403.

Research output: Contribution to journalArticle

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