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Annonacin induces cell cycle-dependent growth arrest and apoptosis in estrogen receptor-α-related pathways in MCF-7

Yu-Min Ko1, Tung-Ying Wu, Yang-Chang Wu

  • 1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.

Journal of Ethnopharmacology
|August 16, 2011
PubMed
Abstract

Insights

Annonacin, derived from pawpaw and soursop, inhibits estrogen receptor-α (ERα)-positive breast cancer cell growth and induces apoptosis. This natural compound shows promise in overcoming tamoxifen resistance and reducing tumor growth in vivo.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Tamoxifen resistance is a significant challenge in treating estrogen receptor-α (ERα)-positive breast cancers.
  • Pawpaw and soursop are annonaceous plants with known anticancer properties used in complementary medicine.
  • Annonacin, a key acetogenin from these plants, was investigated for its therapeutic potential in breast cancer.

Purpose of the Study:

  • To investigate the effects of annonacin on ERα-positive breast cancer cells (MCF-7).
  • To determine annonacin's impact on cell survival, cell death, and key molecular pathways.
  • To evaluate annonacin's efficacy in a preclinical mouse model of breast cancer.

Main Methods:

  • Cell viability and apoptosis assays were performed on MCF-7 cells treated with annonacin.
  • Western blotting was used to analyze protein expression levels of ERα, cyclins, and apoptosis markers.
  • The effects of annonacin on ERα transcriptional activity and signaling pathways (ERK, JNK, STAT3) were assessed.
  • Annonacin was administered to MCF-7 xenografts in nude mice to evaluate its in vivo anti-tumor activity.

Main Results:

  • Annonacin significantly reduced cell survival and increased cell death in MCF-7 cells, exhibiting additive effects with 4-hydroxytamoxifen.
  • Annonacin induced G(0)/G(1) cell cycle arrest, modulated p21(WAF1), p27(kip1), and cyclin D1 protein levels, and promoted apoptosis by downregulating Bcl-2.
  • In vivo, annonacin significantly inhibited MCF-7 xenograft tumor growth and decreased ERα, cyclin D1, and Bcl-2 protein expression within the tumors.

Conclusions:

  • Annonacin effectively induces growth arrest and apoptosis in ERα-positive breast cancer cells via ERα-related pathways.
  • The combination of annonacin and 4-hydroxytamoxifen demonstrates additive effects on inhibiting cell survival and ERα transcriptional activity.
  • Annonacin exhibits significant anti-tumor activity in vivo, making it a potential therapeutic agent for tamoxifen-resistant breast cancer.

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