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Inostamycin enhanced TRAIL-induced apoptosis through DR5 upregulation on the cell surface

Kohta Yamamoto1, Masafumi Makino, Ramida Watanapokasin

  • 1Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.

The Journal of Antibiotics
|April 5, 2012
PubMed

Insights

Inostamycin combined with TRAIL synergistically kills cancer cells by increasing DR5 expression. This combination therapy may overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits selective cancer cell cytotoxicity, but TRAIL resistance limits its therapeutic use.
  • Developing agents that enhance TRAIL efficacy is crucial for overcoming cancer cell resistance.
  • Small molecules potentiating TRAIL-induced apoptosis are strategic candidates for combination cancer therapy.

Purpose of the Study:

  • To investigate the synergistic effect of inostamycin and TRAIL on cancer cells.
  • To elucidate the molecular mechanisms underlying inostamycin's potentiation of TRAIL-induced apoptosis.
  • To evaluate the potential of inostamycin-TRAIL combination therapy in overcoming TRAIL resistance.

Main Methods:

  • HCT116 cells were treated with inostamycin and TRAIL, individually and in combination.
  • Caspase-dependent apoptosis was assessed.
  • DR5 expression levels and cell surface localization were analyzed.
  • DR5 knockdown was performed to evaluate its role in apoptosis induction.

Main Results:

  • Combined inostamycin and TRAIL treatment synergistically induced caspase-dependent apoptosis in HCT116 cells.
  • Inostamycin upregulated the expression of DR5, a key receptor for TRAIL.
  • Knockdown of DR5 abrogated the synergistic apoptotic effect, indicating DR5's essential role.
  • Inostamycin increased the cell surface expression of DR5, enhancing TRAIL binding and downstream signaling.

Conclusions:

  • Inostamycin potentiates TRAIL-induced apoptosis by upregulating DR5 expression and increasing its cell surface localization.
  • The combination of inostamycin and TRAIL demonstrates a promising strategy to overcome TRAIL resistance in cancer.
  • This approach holds potential for developing novel combination cancer therapies.

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