TRAIL recombinant adenovirus triggers robust apoptosis in multidrug-resistant HL-60/Vinc cells preferentially through death receptor DR5.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because of its highly selective apoptosis-inducing action on neoplastic versus normal cells. However, some cancer cells express resistance to recombinant soluble TRAIL. To overcome this problem, we used a TRAIL adenovirus (Ad5/35-TRAIL) to induce apoptosis in a drug-sensitive and multidrug-resistant variant of HL-60 leukemia cells and determined the molecular mechanisms of Ad5/35-TRAIL-induced apoptosis. Ad5/35-TRAIL did not induce apoptosis in normal human lymphocytes, but caused massive apoptosis in acute myelocytic leukemia cells. It triggered more efficient apoptosis in drug-resistant HL-60/Vinc cells than in HL-60 cells. Treating the cells with anti-DR4 and anti-DR5 neutralizing antibodies (particularly anti-DR5) reduced, whereas anti-DcR1 antibody enhanced, the apoptosis triggered by Ad5/35-TRAIL. Whereas Ad5/35-TRAIL induced apoptosis in both cell lines through activation of caspase-3 and caspase-10, known to link the cell death receptor pathway to the mitochondrial pathway, it triggered increased mitochondrial membrane potential change (m) only in HL-60/Vinc cells. Ad5/35-TRAIL also increased the production of reactive oxygen species, which play an important role in apoptosis. Therefore, using Ad5/35-TRAIL may be an effective therapeutic strategy for eliminating TRAIL-resistant malignant cells and these studies may provide clues to treat and eradicate acute myelocytic leukemias.
Wu
Ching-Huang
CH
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kao
Ching-Hai
CH
Safa
Ahmad R
AR
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells / Q000187:drug effects / Q000821:virology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D011995:Recombination, Genetic
D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C114109:TNFRSF21 protein, human