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Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells

Shan Zhao1, Chun-Min Ma, Chuan-Xu Liu

  • 1Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai 200025, PR China.

International Journal of Molecular Medicine
|July 25, 2012
PubMed

Insights

Isobatachalone (IBC) and chloroquine induce myeloma cell death via apoptosis and autophagy. Inhibiting autophagy or protein kinase Cδ (PKCδ) enhances this effect, suggesting a novel treatment strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Multiple myeloma is an incurable cancer requiring novel therapeutic strategies.
  • Isobatachalone (IBC), a natural chalcone, shows promise in inducing cancer cell death.

Purpose of the Study:

  • To investigate the therapeutic potential of isobavachalcone (IBC) in multiple myeloma.
  • To elucidate the mechanisms of IBC-induced cell death, including its interaction with autophagy and apoptosis pathways.

Main Methods:

  • Myeloma cells were treated with IBC, and cell death was assessed.
  • Autophagy was inhibited using genetic (beclin-1 knockdown) and pharmacological (3-methyladenine, bafilomycin A, chloroquine) methods.
  • Mitochondrial membrane potential, caspase activation, PARP cleavage, and protein kinase Cδ (PKCδ) activation were analyzed.
  • The effect of the combination therapy on normal peripheral blood mononuclear cells was evaluated.

Main Results:

  • IBC induced apoptosis- and autophagy-related cell death in myeloma cells.
  • Inhibition of autophagy significantly enhanced IBC-induced cell death.
  • The combination of chloroquine and IBC led to mitochondrial membrane potential collapse, caspase activation, PARP cleavage, and PKCδ activation.
  • Inhibition of PKCδ suppressed the apoptosis induced by chloroquine and IBC co-treatment.
  • The combination therapy showed minimal toxicity to normal peripheral blood mononuclear cells.

Conclusions:

  • Isobatachalone (IBC) induces myeloma cell death through apoptosis and autophagy.
  • The combination of chloroquine and IBC enhances cell death via mitochondrial dysfunction and PKCδ activation.
  • This combination represents a potentially effective and specific novel treatment regimen for multiple myeloma.

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