HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy.

Abstract
Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma through correlation of XIAP expression with disease stage, RAS/RAF mutational status, clinical outcome, and susceptibility to endoplasmic reticulum (ER) stress-induced cell death. XIAP expression and N-RAS/B-RAF mutational status were retrospectively determined in a cohort of 55 primary cutaneous melanocytic lesions selected and grouped according to the American Joint Committee on Cancer staging system. Short hairpin RNA interference of XIAP was used to analyze the effect of XIAP expression on ER stress-induced apoptosis in response to fenretinide or bortezomib in vitro. The results showed that XIAP positivity increased with progressive disease stage, although there was no significant correlation between XIAP positivity and combined N-RAS/B-RAF mutational status or clinical outcome. However, XIAP knockdown significantly increased ER stress-induced apoptosis of melanoma cells in a caspase-dependant manner. The correlation of XIAP expression with disease stage, as well as data showing that XIAP knockdown significantly increases fenretinide and bortezomib-induced apoptosis of metastatic melanoma cells, suggests that XIAP may prove to be an effective therapeutic target for melanoma therapy.
AuthorsEmma L Hiscutt, David S Hill, Shaun Martin, Ryan Kerr, Andrew Harbottle, Mark Birch-Machin, Christopher P F Redfern, Simone Fulda, Jane L Armstrong, Penny E Lovat
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 130 Issue 9 Pg. 2250-8 (Sep 2010) ISSN: 1523-1747 [Electronic] United States
PMID20520630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Boronic Acids
  • Pyrazines
  • RNA, Small Interfering
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Fenretinide
  • Bortezomib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects, physiology)
  • Boronic Acids (pharmacology)
  • Bortezomib
  • Drug Resistance, Neoplasm
  • Endoplasmic Reticulum (physiology)
  • Female
  • Fenretinide (pharmacology)
  • Gene Expression Regulation, Neoplastic
  • Genes, ras (physiology)
  • Humans
  • In Vitro Techniques
  • Male
  • Melanoma (drug therapy, metabolism, pathology)
  • Middle Aged
  • Mutation (genetics)
  • Nevus, Pigmented (drug therapy, metabolism, pathology)
  • Proto-Oncogene Proteins B-raf (genetics)
  • Pyrazines (pharmacology)
  • RNA, Small Interfering
  • Skin Neoplasms (drug therapy, metabolism, pathology)
  • Stress, Physiological (physiology)
  • X-Linked Inhibitor of Apoptosis Protein (antagonists & inhibitors, genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: