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Preferential target is mitochondria in alpha-mangostin-induced apoptosis in human leukemia HL60 cells

Kenji Matsumoto1, Yukihiro Akao, Hong Yi

  • 1Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. kmatsumo@giib.or.jp

Bioorganic & Medicinal Chemistry
|October 23, 2004
PubMed

Insights

Alpha-mangostin, a compound from mangosteen, triggers apoptosis in cancer cells by targeting mitochondria. Its structure is key to this effect, suggesting potential for cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Alpha-mangostin, a xanthone from mangosteen, previously demonstrated caspase-3-dependent apoptosis induction in HL60 cells.
  • Further investigation into the precise mechanism of alpha-mangostin-induced apoptosis is warranted.

Purpose of the Study:

  • To elucidate the mechanism of alpha-mangostin-induced apoptosis in HL60 cells.
  • To explore the structure-activity relationship of xanthone derivatives regarding their apoptotic potency.

Main Methods:

  • HL60 cells were treated with alpha-mangostin.
  • Assays were performed to measure caspase activation (caspase-9, -3, -8), mitochondrial dysfunction (swelling, membrane potential loss, ATP decrease, ROS accumulation), and release of apoptotic factors (cytochrome c, AIF).
  • Expression of bcl-2 family proteins and activation of MAP kinases were assessed. Structure-activity relationship studies were conducted on xanthone derivatives.

Main Results:

  • Alpha-mangostin activated caspase-9 and -3, but not caspase-8, indicating involvement of the mitochondrial pathway.
  • Mitochondrial dysfunction, including loss of membrane potential (deltapsim), ATP depletion, ROS generation, and release of cytochrome c/AIF, occurred rapidly (1-2 hours).
  • Cytotoxicity correlated with deltapsim decrease, and hydroxyl group replacement by methoxy group significantly reduced potency.

Conclusions:

  • Alpha-mangostin preferentially targets mitochondria, initiating apoptosis in HL60 cells via the intrinsic pathway.
  • The structure of alpha-mangostin, particularly the hydroxyl group, is crucial for its apoptotic activity.
  • Alpha-mangostin and its analogs show promise as candidates for cancer prevention and therapy.

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