Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1.
Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.
MacFarlane
M
M
MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester, UK.
Inoue
S
S
Kohlhaas
S L
SL
Majid
A
A
Harper
N
N
Kennedy
D B J
DB
Dyer
M J S
MJ
Cohen
G M
GM
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D047630:Depsipeptides / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells
D051017:Apoptosis Regulatory Proteins; D047630:Depsipeptides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D006655:Histone Deacetylases