Author(s): Christodoulopoulos G, Muller C, Salles B, Kazmi R, Panasci L
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Abstract In this study, we examined the ability of wortmannin to modulate chlorambucil (CLB) cytotoxicity in lymphocyte samples from patients with B-cell chronic lymphocytic leukemia (B-CLL). It has been suggested previously that enhanced cross-link repair is a primary mechanism of resistance to nitrogen mustards (NMs) in B-CLL. DNA-dependent protein kinase (DNA-PK) is involved in the repair of double-strand breaks and in rejoining steps in recombination mechanisms. Mutants defective in this process are hypersensitive to alkylating agents. We have recently demonstrated that the activity of DNA-PK is a determinant in the cellular response of B-CLL to CLB. The DNA-PK gene has homology to the P110 phosphatidylinositol 3-kinase (PI 3-K). Wortmannin, an inhibitor of P110 PI 3-K, also inhibits DNA-PK activity in vitro. We investigated the effect of wortmannin on DNA-PK activity and CLB toxicity in the lymphocytes from 11 patients with B-CLL. Our results demonstrate that DNA-PK activity is decreased after exposure to wortmannin in a dose-dependent manner. Wortmannin, at nontoxic concentrations, synergistically sensitized B-CLL lymphocytes to the effects of CLB. Moreover, we observed a significant correlation when we compared the fold decrease in DNA-PK activity and the synergistic value (I), obtained when wortmannin was used at 0.1 microM. In the resistant B-CLL lymphocyte samples, there was a highly significant correlation between the ability of wortmannin at 0.1 and 0.25 microM to decrease the level of DNA-PK activity and to increase CLB sensitivity. In a model of primary human tumor cells, our findings suggest that the inhibition of DNA-PK activity may be a powerful way to overcome resistance to NMs such as CLB and point to new possibilities to improve the effectiveness of NM therapy.
This article was published in Cancer Res
and referenced in Journal of Cancer Science & Therapy