Beta-lapachone (β-Lap; 3,4-dihydro-2, 2-dimethyl-2H-
naphthol[1, 2-b]
pyran-5,6-dione) is a novel anti-
cancer drug under phase I/II clinical trials. β-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human
cancer cells in vitro and in vivo. The mechanisms underlying the β-Lap toxicity against
cancer cells has been controversial. The most recent view is that β-Lap, which is a
quinone compound, undergoes two-electron reduction to
hydroquinone form utilizing
NAD(P)H or
NADH as electron source. This two-electron reduction of β-Lap is mediated by
NAD(P)H:
quinone oxidoreductase (NQO1), which is known to mediate the reduction of many
quinone compounds. The
hydroquinone forms of β-Lap then spontaneously oxidizes back to the original oxidized β-Lap, creating futile cycling between the oxidized and reduced forms of β-Lap. It is proposed that the futile recycling between oxidized and reduced forms of β-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced β-Lap is converted first to one-electron reduced β-Lap, i.e., semiquinone β-Lap (SQ)(·-) causing production of
reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of
NAD(P)H and
NADH as a result of futile cycling between the
quinone and
hydroquinone forms of β-Lap causes severe disturbance in cellular metabolism leading to apoptosis and
necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of
NAD(P)H/
NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in
cancer cells has been found to be higher than that in normal cells indicating that β-Lap may be preferentially toxic to
cancer cells relative to non-
cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that β-Lap and ionizing radiation kill
cancer cells in a synergistic manner. Indications are that irradiation of
cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to β-Lap. In addition, β-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental
tumors growing in the legs of mice with irradiation and
intraperitoneal injection of β-Lap suppressed the growth of the
tumors in a manner more than additive. Collectively, β-Lap is a potentially useful anti-
cancer drug, particularly in combination with
radiotherapy.