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

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a possible therapeutic agent for cancer treatment. This is because of its selective cytotoxicity against various cancer cells without a detrimental effect on normal cells. However, recent studies have reported that the potential application of TRAIL in cancer therapy is limited, as many cancer cells have been found to be resistant to TRAIL. Therefore, small molecule compounds that potentiate the cytotoxicity of TRAIL would be strategic candidates for therapeutic applications in combination with TRAIL. Here we found that a combined treatment of inostamycin and TRAIL synergistically induced caspase-dependent apoptosis in HCT116 cells. Inostamycin upregulated DR5, and a knockdown of DR5 suppressed the apoptosis that was synergistically induced by co-treatment with inostamycin and TRAIL. Moreover, inostamycin increased the expression of DR5 on the cell surface. Therefore, inostamycin-increased cell surface expression of DR5 may have contributed to the enhancement of TRAIL-induced apoptosis. Our study suggests that combined treatment with inostamycin and TRAIL may offer a strategy to overcome TRAIL resistance in tumor cells.
AuthorsKohta Yamamoto, Masafumi Makino, Ramida Watanapokasin, Etsu Tashiro, Masaya Imoto
JournalThe Journal of antibiotics (J Antibiot (Tokyo)) Vol. 65 Issue 6 Pg. 295-300 (Jun 2012) ISSN: 1881-1469 [Electronic] England
PMID22472572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Furans
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • inostamycin
Topics
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Survival (physiology)
  • Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Drug Synergism
  • Flow Cytometry
  • Furans (pharmacology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • HCT116 Cells
  • Humans
  • RNA, Neoplasm (chemistry, genetics)
  • RNA, Small Interfering (administration & dosage, genetics)
  • Real-Time Polymerase Chain Reaction
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics, metabolism)
  • TNF-Related Apoptosis-Inducing Ligand (pharmacology)
  • Up-Regulation (drug effects)

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