CLL Apoptosis Induced by Nitric Oxide Synthase Inhibitors

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CLL cell apoptosis induced by nitric oxide synthase inhibitors:

Correlation with lipid solubility and NOS1 dissociation constant.

Levesque MC, Ghosh DK, Beasley BE, Chen Y, Volkheimer AD, O'Loughlin

CW, Gockerman JP, JO, Weinberg JB.

Department of Medicine, Division of Rheumatology and Clinical

Immunology, Duke University and Durham VA Medical Centers, Durham, NC,

United States.

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.

PMID: 18180035 [PubMed - as supplied by publisher]