Affiliations: Department of Foods and Nutrition, Purdue University,
West Lafayette, IN, USA | Department of Medicinal Chemistry and Molecular
Pharmacology, Purdue University, West Lafayette, IN, USA
Note: [] Address for correspondence: D.J. Morré, Department of
Medicinal Chemistry and Molecular Pharmacology, HANS Life Sciences Research
Building, Purdue University, 201 South University Street, West Lafayette, IN
47907-2064, USA. Fax: +1 765 494 4007; E-mail: [email protected]
Abstract: Phenoxodiol, an ENOX2 inhibitor, alters cytosolic NADH levels to
initiate a regulatory cascade linking sphingolipid metabolism and the PI3K/Akt
pathway to programmed cell death. Specifically, the pyridine nucleotide
products of plasma membrane redox, NAD^{+} and NADH,
directly modulate in a recriprocal manner two key plasma membrane enzymes. NADH
stimulation of sphingomyelinase and NADH inhibition of sphingosine kinase
potentially lead to G_{1} arrest (increase in ceramide) and
apoptosis (loss of sphingosine-1-phosphate). The findings link plasma membrane
electron transport and the anticancer action of several clinically-relevant
anticancer agents targeted to ENOX2 such as phenoxodiol. Growth inhibition by
phenoxodiol is unaffected by inhibitors of protein or mRNA synthesis. Findings
with okadiaic acid, an inhibitor of serine/threonine phosphatases, suggest that
hyperphosphorylation of intracellular substrates does not affect the action of
phenoxodiol on ENOX2. Our findings and those of others are consistent with
operation of the FAS signaling pathway of apoptosis and its suppression by
sphingosine-1-phosphate. The prevailing hypothesis is that products of Akt
activation, c-FLIP and XIAP, which exhibit anticaspase activities to block FAS
signaling when sphingosine-1-phospate is elevated, are down regulated to permit
apoptosis when sphingosine-1-phosphate is decreased by inhibition of
sphingosine kinase under conditions of elevated cytosolic NADH associated with
anticancer drug inhibition of ENOX2.
DOI: 10.3233/BIO-2009-1079
Journal: BioFactors, vol. 34, no. 3, pp. 253-260, 2009
