NAD⁺/NADH and/or CoQ/CoQH₂ ratios from plasma membrane electron transport may determine ceramide and sphingosine‐1‐phosphate levels accompanying G₁ arrest and apoptosis

Abstract

To elucidate possible biochemical links between growth arrest from antiproliferative chemotherapeutic agents and apoptosis, our work has focused on agents (EGCg, capsaicin, cis platinum, adriamycin, anti-tumor sulfonylureas, phenoxodiol) that target tNOX. tNOX is a cancer-specific cell surface NADH oxidase (ECTO-NOX protein), that functions in cancer cells as the terminal oxidase for plasma membrane electron transport. When tNOX is active, coenzyme Q(10) (ubiquinone) of the plasma membrane is oxidized and NADH is oxidized at the cytosolic surface of the plasma membrane. However, when tNOX is inhibited and plasma membrane electron transport is diminished, both reduced coenzyme Q(10) (ubiquinol) and NADH would be expected to accumulate. To relate inhibition of plasma membrane redox to increased ceramide levels and arrest of cell proliferation in G(1) and apoptosis, we show that neutral sphingomyelinase, a major contributor to plasma membrane ceramide, is inhibited by reduced glutathione and ubiquinone. Ubiquinol is without effect or stimulates. In contrast, sphingosine kinase, which generates anti-apoptotic sphingosine-1-phosphate, is stimulated by ubiquinone but inhibited by ubiquinol and NADH. Thus, the quinone and pyridine nucleotide products of plasma membrane redox, ubiquinone and ubiquinol, as well as NAD(+) and NADH, may directly modulate in a reciprocal manner two key plasma membrane enzymes, sphingomyelinase and sphingosine kinase, potentially leading to G(1) arrest (increase in ceramide) and apoptosis (loss of sphingosine-1-phosphate). As such, the findings provide potential links between coenzyme Q(10)-mediated plasma membrane electron transport and the anticancer action of several clinically-relevant anticancer agents.

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

“…3,26 DeLuca et al 13 proposed that inhibition of PMET via tNOX results in increased levels of intracellular NADH and membrane ubiquinol, inhibiting sphingosine kinase and increasing membrane ceramide levels, which induce G1 arrest and apoptosis. In contrast, activity of constitutively-expressed cell surface NADH-oxidase, CNOX, present on both cancer and non-cancer cells, was said to be unaffected by phenoxodiol; thus, phenoxodiol has been heralded as a pan-cancer drug.…”

“…1,2 Phenoxodiol has been referred to as a pan-cancer drug, 3 causing apoptosis in cancer cell lines and murine cancer models via both intrinsic and extrinsic pathways. [4][5][6][7][8][9][10][11][12][13][14] Plasma membrane electron transport (PMET) has been shown to be a target of phenoxodiol in several studies with cancer cell lines. 3,13,15 PMET consists of an outer membrane (surface) NADH-oxidoreductase, redox-recycling plasma membrane ubiquinone and an inner membrane NADH-oxidoreductase.…”

“…[4][5][6][7][8][9][10][11][12][13][14] Plasma membrane electron transport (PMET) has been shown to be a target of phenoxodiol in several studies with cancer cell lines. 3,13,15 PMET consists of an outer membrane (surface) NADH-oxidoreductase, redox-recycling plasma membrane ubiquinone and an inner membrane NADH-oxidoreductase. 16 PMET plays a vital role in maintaining both plasma membrane and intracellular redox balances to support continued cell survival, function and growth of fast proliferating cells.…”

“…16 PMET plays a vital role in maintaining both plasma membrane and intracellular redox balances to support continued cell survival, function and growth of fast proliferating cells. 13,17,18 Most cancer cells actively increase glucose uptake to meet increased energy demands; this is associated with increased NADH recycling to maintain intracellular NADH/NAD + ratios. Cells that generate most of their energy through oxidative phosphorylation recycle NADH mainly through mitochondrial electron transport.…”

Chapter Twenty‐Two Mechanisms and Methods in Glucose Metabolism and Cell Death

“…There is a specific form of cell death, eryptosis, in nonnucleate cells such as red blood cells that is apoptosis-like in morphology (Lang et al, 2006). Eryptosis requires caspases as well as Ca 2+ -dependent channels and formation of ceramide (Lang et al, 2006), all of which can be affected by the status of glucose metabolism and levels of ATP (De Luca et al, 2005;Henquin, 2000). Therefore, eryptosis is also an energy-dependent form of cell death.…”