Radiat Oncol J.  2013 Jun;31(2):57-65. 10.3857/roj.2013.31.2.57.

Enhancement of radiation effect using beta-lapachone and underlying mechanism

Affiliations
  • 1Department of Radiation Oncology, Inje University College of Medicine, Busan, Korea.
  • 2Department of Radiation Oncology, Dong-A University College of Medicine, Busan, Korea. hyslee@dau.ac.kr
  • 3Department of Biochemistry, Kangwon National University, Chuncheon, Korea.
  • 4Radiobiology Laboratory, Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, MN, USA.

Abstract

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

Keyword

Beta-Lapachone; Radiation; NQO1; Radiosensitivity; Radiation damage

MeSH Terms

Animals
Apoptosis
Benzoquinones
Cell Death
Electrons
Humans
Hydroquinones
Injections, Intraperitoneal
Leg
Mice
NAD
Naphthoquinones
Necrosis
Radiation Tolerance
Radiation, Ionizing
Reactive Oxygen Species
Recycling
Substrate Cycling
Benzoquinones
Hydroquinones
NAD
Naphthoquinones
Reactive Oxygen Species
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