Resistance to doxorubicin is reversible on treatment with HDACis in human BL-xenografted mice. (A) Treatment of BL cells with 5-Aza or vorinostat resulted in BIM reexpression (Figure 1E). Subsequent incubation of these cells with doxorubicin led to a higher decrease in cell viability in Seraphina and Jijoye cells treated with vorinostat versus 5-Aza therapy. (B) Treatment of the BL unmethylated cell lines Balm9 and DG75 with vorinostat did not increase BIM expression. In addition, no differences in cell viability were observed between doxorubicin and doxorubicin plus vorinostat therapies in these cells. (C) Experimental design and Kaplan-Meier survival curves for 5 mouse cohorts transplanted with Seraphina cells with BIM hypermethylation and treated with vehicle (DMSO), low-dose vorinostat, doxorubicin, low-dose vorinostat plus doxorubicin, and low-dose vorinostat plus doxorubicin and cyclophosphamide. Those receiving the combination of low-dose vorinostat plus doxorubicin and cyclophosphamide resulted in the longest OS compared with the other subgroups. (D) An increase in the apoptotic rates was observed on treatment with vorinostat and doxorubicin in Seraphina and Jijoye cells compared with other in vitro treatments, as determined by annexin V/propidium iodide staining. (E) Representative study of the induction of apoptosis in Seraphina cells after treatment with vorinostat plus doxorubicin, as shown by caspase 3 and 9 activation and increased PARP expression. (F) Micro-PET studies showed that mice treated with vorinostat plus doxorubicin and with vorinostat plus doxorubicin and cyclophosphamide presented a significant decrease in tumor activity compared with mice treated with single vorinostat or doxorubicin, which was correlated with prolonged survival. Images were taken 2 weeks after treatment with the corresponding compound.