Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo). Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo).

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Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo). Five-day exposure to decitabine (DAC) sensitizes cells to doxorubicin (Doxo). A, activity of caspase-7/3 (y-axis, fold to control) in OCI-Ly1 and Karpas422 cells preexposed to vehicle or decitabine 100 nmol/L for 5 days and treated with water (UT) or five concentrations of doxorubicin. B, dose reduction plot for doxorubicin GI50 (fold decitabine to vehicle, x-axis) in the panel of eight doxorubicin-resistant cell lines after exposure to decitabine for 5 days compared with their respective vehicle-treated cells. Change in GI50 is represented by fold to vehicle. The red arrow indicates the favorable dose reduction zone. Data represent mean of triplicate experiments. C, AUC of tumor growth curves in OCI-Ly1 xenografted mice treated with vehicle (V; PBS, n = 8), doxorubicin 0.6 mg/kg twice a week (n = 8), decitabine 15 mg/m2 daily (n = 8), or their sequential combination (n = 7). Treatment was initiated when tumors reached approximately 100 mm3, drugs were administered sequentially during the first 10 days, and mice were further followed without treatment until the end of the experiment at day 20. P values represent the comparison of tumor AUC volumes with vehicle and between decitabine and the combination. D, immunohistochemistry (IHC) for phospho-H2AX in the lymphoma tissues of the mice from C. ×40 photographs (bar = 400 μm; left) and ×100 photographs (bar = 100 μm; right). Quantification of positive cells (in %) is shown as inserts. E, CD19+ single-cell suspensions from lymph node biopsies of four refractory DLBCL specimens were exposed to decitabine 100 nmol/L for 48 hours followed by either doxorubicin 0.6 μmol/L, doxorubicin 1.2 μmol/L, or vehicle for additional 48 hours. Cell viability at 96 hours (normalized to 48 hours of vehicle or decitabine-treated cells) is shown on the y-axis. The experiment was carried out in duplicate. Thomas Clozel et al. Cancer Discovery 2013;3:1002-1019 ©2013 by American Association for Cancer Research