Etoposide-mediated sensitization of squamous cell carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced loss in mitochondrial membrane potential.
Squamous cell carcinoma (SCC) cell lines (MIT7-x(L), MIT8, and MIT16) that overexpress Bcl-x(L) have been demonstrated to show resistance to multiple chemotherapeutic drugs. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which belongs to the TNF family of proteins, induces apoptosis in tumor, but not in normal, cells. In the present study, we examined whether etoposide sensitizes tumor cells with multiple-drug-resistance to TRAIL-induced apoptosis. Sequential treatment with etoposide and TRAIL resulted in a synergistically induced cell death in the two resistant lines (MIT7-x(L) and MIT16) but not MIT8, as assessed by WST-8 assay. As expected, MIT7 cells (a drug-sensitive line) were sensitive to the combined treatment. The cell death caused by both etoposide and TRAIL appears to involve apoptosis, since the combined treatment caused a loss in mitochondrial membrane potential (DeltaPsim), which is closely associated with apoptosis induction. The density of the TRAIL-receptors (TRAIL-Rs) was not appreciably modulated by the etoposide treatment, suggesting that etoposide targets molecule(s) downstream of the TRAIL-Rs. Regardless of the molecular mechanisms underlying the cell death, sequential treatment with etoposide and TRAIL could be useful in the design of treatment modalities for patients with SCC, especially those with elevated levels of Bcl-x(L).
Itoh
M
M
Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan.
Noutomi
T
T
Toyota
H
H
Mizuguchi
J
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D005047:Etoposide