Preferntial Damage in Tumors by Beta-lapachone is Enhanced by Radiation and Heat

초록

Beta-lapachone (B-lap)(3,4-dimethyl-2H-naphthole[1,2-b]pyran-5,6-dione) iis a onaphthoquinone originally obtained from the bark of Lapacho tree in South America. It is a potent experimental anti-cancer drug preferentially effective against cancer cells. It has been reported that B-lap inhibits Topoisomerase I or Topoisomerase II, thereby kills cells and also sensitizes cells to ionizing radiation (IR) or certain chemotherapy drugs. Recent results, however, indicated that the NAD(P):quinone oxidoreducutase (NQO1) induces futile cycling between B-lap and hydoquinone form of B-lap utilizing NADH and NAD(P)H as electron source. Severe delpetion of NADH and NAD(P)H appears to activate Ca2+- dependent calpain-like protease inducing caspase-independent apopopsis. We however, observed that B-lap also induces caspase-dependent apoptosis, particularly when B-lap concentration is relatively low. We therefore hypothesize that when NADH and NAD(P)H are not exhausted enough to activate calpain-like protease, caspase-dependent apoptos initiated by reactive oxygen species (ROS) is the major mode of cell death caused by B-lap. It appears that the hydroquinone B-lap formed by the mediation of NQO1 undergo one-electron oxidation to semiquinone B-lap(SQ)-, which then leads to redox cycling resulting in generation of ROS. Note that both Ca2+-dependent protease and peneration of ROS are mediated by NQO1. Importantly, the expression of NQO1 in many tumors is far greater than that in adjacent normal tissues suggestion that B-lap would affect preferentially rumors relative to normal tissues. IR has been reported to cause long-lasting increase NQO1 expression and we observed that cells become sensitive to B-lap after IR due to IR-induced increase in NQO1 level.