CLL cell apoptosis induced by nitric oxide synthase inhibitors: correlation with lipid solubility and NOS1 dissociation constant.
Nitric oxide synthase (NOS) inhibitors induce chronic lymphocytic leukemia (CLL) cell apoptosis and have potential as CLL therapeutics. We determined the half-maximal concentration (ED(50)) of 22 NOS inhibitors that induced CLL cell death in vitro. There was a direct correlation of the NOS1 (but not NOS2) dissociation constant (K(d)) and the hydrophobicity partitioning coefficient of each NOS inhibitor and its ED(50). NOS inhibitors that bound tightly to CLL cell NOS1 and were hydrophobic potently induced CLL cell death. CLL cell RNA and protein analyses confirmed CLL cell NOS1 expression. Our studies permit the rational selection of NOS inhibitors for testing as CLL therapeutics.
Levesque
Marc C
MC
Department of Medicine, Division of Rheumatology and Clinical Immunology, Duke University and Durham VA Medical Centers, Durham, NC 27710, United States. marc.levesque@duke.edu
Ghosh
Dipak K
DK
Beasley
Bethany E
BE
Chen
Youwei
Y
Volkheimer
Alicia D
AD
O'Loughlin
Charles W
CW
Gockerman
Jon P
JP
Moore
Joseph O
JO
Weinberg
J Brice
JB
D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D050356:Lipid Metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility
D017931:DNA Primers; D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase