Enhancement of radiation effect using beta-lapachone and underlying mechanism.

ABSTRACT

Beta-lapachone (ß-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. ß-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 ß-Lap toxicity against cancer cells has been controversial. The most recent view is that ß-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 ß-Lap is mediated by NAD(P)Hquinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of ß-Lap then spontaneously oxidizes back to the original oxidized ß-Lap, creating futile cycling between the oxidized and reduced forms of ß-Lap. It is proposed that the futile recycling between oxidized and reduced forms of ß-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced ß-Lap is converted first to one-electron reduced ß-Lap, i.e., semiquinone ß-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 ß-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 ß-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 ß-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 ß-Lap. In addition, ß-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 ß-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, ß-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.