Combined effect of radiation with b-Laphochone against cancer cells

초록

?Lapachone (?Lap) obtained from Lapacho tree has been demonstrated to have potent anti-cancer effects. We have observed that ?Lap is cytotoxic against various cancer cells including FSaII tumor cells of C3H mice, A549 human lung cancer cells, RKO human colon adenocarcinoma cells and PC3 human prostate cancer cells. When A549 cells were exposed to ionizing radiation and treated with ?Lap, the combined effect to cause clonogenic and apoptotic cell death was synergistic. Importantly, such a synergism occurred when cells were treated with ?Lap after irradiating the cells, and not before irradiating the cells, strongly indicating that radiation rendered the cells sensitive to ?Lap. Further studies indicated that cells remain sensitive to ?Lap even 5-10 hours after irradiation and that sensitization to ?Lap occurs with a radiation dose as low as 2.5 Gy. It has been suggested that NAD(p)H:quinone oxidoreductase (NQO1) mediates the ?Lap induced cell death. We observed that the expression of NQO1 in A549 and RKO cells significantly increases for 10 h after 4-Gy irradiation suggesting that the increase in the response of cells to ?Lap after irradiation was due to the increase in the NQO1 level. Western blot analysis demonstrated that ?Lap reduced the level of NFk?in nucleus and increased the release of cytochrome C from mitochondria, which could be the cause of apoptosis. Interestingly, PARP cleavage did not appear to be involved in the ?Lap-induced apoptosis. Treatment of mice bearing RKO tumor xenografts with 12 or 24 mg/kg of ?Lap (i.p) markedly enhanced the radiation-induced tumor growth delay. It has been known that NQO1 is more abundant in neoplastic tissues than in normal tissues indicating that combination of ?Lap and radiation may be an effective regimen to preferentially destroy tumors relative to normal tissues.