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Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway

See-Hyoung Park1, Jongsung Lee2, Mi-Ae Kang3

  • 1Department of Bio and Chemical Engineering, Hongik University, Sejong, Chungcheong 30016, Republic of Korea.

Oncology Letters
|June 22, 2018
PubMed

Insights

Mitoxantrone activates the FOXO3 protein in osteosarcoma cells, inhibiting cancer growth. This DNA-damaging agent induces cancer cell death via an Akt/FOXO3 pathway, offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osteosarcoma chemotherapy has improved, but patient survival rates remain stagnant.
  • Forkhead-box O3 (FOXO3) is a key transcription factor in cancer suppression.
  • Identifying FOXO3 activators could lead to novel cancer therapies.

Purpose of the Study:

  • To screen for small molecules that activate FOXO3.
  • To elucidate the mechanism of FOXO3 activation in osteosarcoma.
  • To evaluate the therapeutic potential of FOXO3 activators.

Main Methods:

  • Utilized a drug discovery platform measuring FOXO3 phosphorylation in osteosarcoma cells.
  • Screened the FDA-approved drug library for FOXO3 activators.
  • Investigated the effect of mitoxantrone (MTZ) on Akt phosphorylation and FOXO3 localization.
  • Assessed MTZ's impact on osteosarcoma cell proliferation and apoptosis, with and without FOXO3 silencing.

Main Results:

  • Mitoxantrone (MTZ), a DNA-damaging agent, was identified as a FOXO3 activator.
  • MTZ treatment decreased Akt phosphorylation (Akt-pS473) and promoted FOXO3 nuclear localization in osteosarcoma cells.
  • MTZ inhibited osteosarcoma cell proliferation in vitro.
  • Silencing FOXO3 significantly reduced MTZ-induced apoptosis in osteosarcoma cells.

Conclusions:

  • Mitoxantrone induces apoptosis in osteosarcoma cells.
  • The mechanism involves the Akt/FOXO3 pathway.
  • MTZ shows promise as a therapeutic agent for osteosarcoma by activating FOXO3.
Keywords:
Aktapoptosisforkhead box O3mitoxantroneosteosarcoma

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