Sequential treatment by ionizing radiation and sodium arsenite dramatically accelerates TRAIL-mediated apoptosis of human melanoma cells.

Abstract

Melanoma is the most lethal form of skin cancer. There is a lack of effective treatments for individuals with advanced disease. Many melanomas exhibit high levels of radioresistance. The direct consequence of gamma-irradiation for most melanoma cells is growth arrest at the G2-M phase of cell cycle. However, radiation-induced signaling pathways may affect numerous additional targets in cancer cells. We show in the present study that gamma-irradiation, as well as alpha-particle exposure, dramatically increases the susceptibility of melanoma cells to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via up-regulation of surface TRAIL-receptor 1/receptor 2 (DR4/DR5) levels and to Fas ligand-mediated apoptosis via up-regulation of surface Fas levels. Additionally, increased dynamin-2 expression after irradiation is critically important in the translocation of death receptor to the cell surface. Moreover, sodium arsenite treatment may up-regulate expression of endogenous TRAIL and induces its translocation to cell surface and further down-regulates cFLIP levels in melanoma cells. We have evaluated the effects of sequential gamma-irradiation and arsenite treatment of melanoma cells for the induction of death signaling. Such treatment results in an efficient TRAIL-mediated apoptosis via a paracrine mechanism. These data highlight the efficacy of combined modality treatment involving radiation and arsenite in clinical management of this often fatal form of skin cancer.

• Authors: Vladimir N Ivanov, Hongning Zhou, Tom K Hei
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 11 Pg. 5397-407 (Jun 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17545621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Arsenites
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Fas Ligand Protein
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• Sodium Compounds
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFSF10 protein, human
• sodium arsenite
• Cycloheximide
• Dynamin II

Topics

• Alpha Particles
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, radiation effects)
• Arsenites (administration & dosage, pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Combined Modality Therapy
• Cycloheximide (pharmacology)
• Drug Synergism
• Dynamin II (biosynthesis, metabolism)
• Fas Ligand Protein (biosynthesis, metabolism)
• Gamma Rays
• Humans
• Melanoma (drug therapy, pathology, radiotherapy)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, metabolism)
• Receptors, Tumor Necrosis Factor (biosynthesis, metabolism)
• Signal Transduction
• Skin Neoplasms (drug therapy, pathology, radiotherapy)
• Sodium Compounds (administration & dosage, pharmacology)
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, pharmacology)