Cancer Therapeutic Applications of ENOX2 Proteins

  • D. James Morré
  • Dorothy M. Morré
Chapter

Abstract

ENOX2 proteins are blocked by quinone-site inhibitors with anticancer activity such as capsaicin, (−)-epigallocatechin-3-gallate, antitumor-sulfonylureas, doxorubicin (Actinomycin D®), and cisplatin. As such they serve as targets for further exploration of anticancer substances and drugs both new and already in clinical use. Especially promising would be ENOX2-targeted early intervention coupled with early detection based on serum presence of ENOX2 transcript variants in sera ( Chap. 12). ENOX2 inhibitors and plasma membrane electron transport (PMET) inhibitors, in general, result in growth stasis normally followed by apoptotic death of cancer cells. As noncancer cells lack ENOX2, they are normally unaffected or less affected. Growth arrest results from blockage of ENOX2-catalyzed protein disulfide-thiol interchange required for cell enlargement in combination with response to elevated ceramide. Proliferating cells unable to enlarge following division due to blocked ENOX2 are unable to divide again due to cell size limitations. Resultant elevations of NADH at the cytosolic surface of the plasma membrane reduce prosurvival levels of sphingosine-1-phosphate through inhibition of sphingosine kinase as well as activation of sphingomyelinase to form ceramide. The result is caspase-3-dependent programmed cell death involving both extrinsic death receptor and intrinsic (mitochondrial) apoptotic pathways. One advantage of ENOX2 and PMET as targets for anticancer drugs is that the ENOX2 proteins are located on the external cell surface and do not need to enter cells to be effective. Efficacious impermeant conjugates have been prepared and tested for doxorubicin, capsaicin, an antitumor sulfonylurea, and an antitumor quassinoid, glaucarubolone.

Keywords

HeLa Cell NADH Oxidase Sphingosine Kinase Plasma Membrane Vesicle Free Doxorubicin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • D. James Morré
    • 1
  • Dorothy M. Morré
    • 1
  1. 1.Mor-NuCo, LLCPurdue Research ParkWest LafayetteUSA

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