Novel use of hyperthermia to enhance the enzymatic activation of anti-cancer drug β-lapachone

초록

NQO1 (NAD(P) H:quinone oxidoreductase), also known as Kiaphorase, is a two-electron reductase and it is involved in remoning harmful quinone from cells, Recently, we as well as others have demonstrated that NQO1 plays a cardinal role in induction of apoptosis and clonogenic death of cancer cells caused by β-lapachone (β-lap), an extract from Lapacho tree. Indications are that NQO1 catalyzed two-electron reduction of β-lap using NAD(P)H or NADH as electron source to β-lap(OH), which then spontaneously oxidizes to β-lap resulting in a futile cycling of electrons between the oxidized and reduced forms of β-lap. The consequent depletion of NAD(P)H or NADH results in depletion of ATP level, release of Ca2+ from the endoplasmic reticulum, activation of ca2+-dependent proteases, i.e. Calpain, and cytochrome c release from mitochondria leading to apoptoeic or necrotic cell death. Another possible cytocidal signaling caused by β-lap treatment is that some β-lap(HQ) may not directly oxidize back to β-lap, but first oxidizes to one-electron reduced intermediate, i.e. semiquinone β-lap(SQ)-, thereby eliciting redox cycling and generating wuper oxides and H2O2 in the presence of oxygen molecules.