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Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related

Wentao Jia1, Chunrong Yu, Mohamed Rahmani

  • 1Division of Hematology/Oncology, MCV Station Box 230, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA 23298, USA.

Blood
|May 10, 2003
PubMed

Insights

The heat shock protein 90 (Hsp90) antagonist 17-AAG enhances the cancer cell killing effects of the Chk1 inhibitor UCN-01 in human leukemia cells. This combination therapy targets key cell survival pathways, leading to synergistic apoptosis induction.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Heat shock protein 90 (Hsp90) is crucial for the stability of client proteins involved in cancer cell survival.
  • UCN-01 is a Chk1 inhibitor that also affects protein kinase C (PKC) signaling.
  • 17-AAG is an Hsp90 antagonist that destabilizes numerous oncoproteins.

Purpose of the Study:

  • To investigate the synergistic effects of combining the Hsp90 antagonist 17-AAG with the Chk1 inhibitor UCN-01 in human leukemia cells.
  • To elucidate the underlying molecular mechanisms, including effects on signal transduction pathways and apoptosis.

Main Methods:

  • Human leukemia cell lines (U937, Jurkat, NB4) were treated with 17-AAG and UCN-01, alone or in combination.
  • Mitochondrial membrane potential, cytochrome c release, caspase activation, and apoptosis were assessed.
  • Western blotting was used to analyze the expression and activation of key signaling proteins (Akt, Raf-1, MEK1/2, MAPK, JNK, p38, p34cdc2, Bcl-2, Mcl-1, XIAP).
  • Functional assays involving constitutively active MEK1/2 and Akt constructs were performed.

Main Results:

  • Simultaneous treatment with 17-AAG and UCN-01 synergistically induced apoptosis in multiple human leukemia cell types.
  • This combination led to mitochondrial injury, cytochrome c release, and caspase activation.
  • The synergistic cytotoxicity was associated with diminished Akt activation and down-regulation of the Raf-1/MEK/MAPK pathway.
  • UCN-01's PKC inhibitory activity was not responsible for the synergistic interaction.
  • The combination also caused p34cdc2 dephosphorylation and reduced expression of anti-apoptotic proteins Bcl-2, Mcl-1, and XIAP.

Conclusions:

  • The Hsp90 antagonist 17-AAG potentiates the cytotoxic effects of UCN-01 in various human leukemia cell types.
  • The observed synergy is mediated, in part, by the disruption of both the Akt and Raf-1/MEK/MAP kinase signaling pathways.
  • This combination therapy represents a promising strategy for leukemia treatment by targeting critical cytoprotective pathways.

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