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Assays for Validating Histone Acetyltransferase Inhibitors
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SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling

Yusuke Shibuya1,2, Kei Kudo1,2, Kristen P Zeligs1,3,4

  • 1Women's Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Cancers
|February 25, 2023
PubMed

Insights

Combining SMAC mimetics with HDAC inhibitors shows promise for treating recurrent ovarian cancer. This drug combination restores apoptosis and leads to tumor death, offering new hope for patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Overexpression of inhibitor of apoptosis (IAP) proteins is linked to poor survival in ovarian cancer patients.
  • Recurrent ovarian cancers exhibit resistance to apoptosis due to dysregulated IAP proteins.

Purpose of the Study:

  • To identify synergistic drug combinations with the SMAC mimetic birinapant for recurrent ovarian cancer.
  • To evaluate the efficacy and underlying mechanisms of SMAC mimetics combined with HDAC inhibitors.

Main Methods:

  • High-throughput screening was employed to identify synergistic drug combinations with birinapant.
  • In vitro and in vivo studies were conducted to assess the combination therapy's effects.
  • Mechanistic studies investigated pathways including caspase activation, TNF-α upregulation, and NF-kB signaling.

Main Results:

  • SMAC mimetics in combination with HDAC inhibitors demonstrated remarkable synergy against recurrent ovarian cancer.
  • The combination therapy resulted in increased caspase activation and TNF-α upregulation.
  • Convergent signaling pathways, including alternative NF-kB signaling, were activated by the combination.

Conclusions:

  • The combination of SMAC mimetics and HDAC inhibitors offers a promising therapeutic strategy for recurrent ovarian cancer.
  • These findings provide a strong rationale for integrating SMAC mimetics and HDAC inhibitors into clinical trials for ovarian cancer treatment.
Keywords:
HDAC inhibitorIAP inhibitorSMAC mimeticsTNF-αovarian cancer

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