Figure 8. Obatoclax displays a strong chemosensitizing activity in multidrug-resistant primary ALL cells from poor risk patients.

(A) Primary ALL cells from 5 PPR patients and 3 prednisone-good-responder patients were cocultured with hTERT-immortalized bone marrow stroma cells and treated with either dexamethasone (1 μM) alone or in combination with obatoclax (10% IC₅₀) in the presence or absence of 3-MA, nec-1, or zVAD.fmk for 72 hours. Cell viability was assessed by 7AAD staining and flow cytometry. Data are shown as mean ± SD of 2 independent experiments. In combination experiments, values were normalized to cells treated with compounds and/or inhibitors alone at indicated dose. (B) Primary ALL cells from 4 VHR, 1 high risk (HR), and 3 standard risk (SR) patients were cocultured with hTERT-immortalized bone marrow stroma cells and treated with either daunorubicin, vincristine, or cytarabine (araC) alone or in combination with obatoclax (10% IC₅₀) in the presence or absence of 3-MA, nec-1, or zVAD.fmk for 72 hours. Cell viability was assessed by 7AAD staining and flow cytometry. Data are shown as mean ± SD of 2 independent experiments. ***P < 0.05 (A and B). (C) Percentage of event-free survival (pEFS) of NSG mice after xenotransplantation with primary cells from 2 PPR patients with VHR-ALL (VHR-02, n = 8; patient VHR-01, n = 6; Supplemental Table 2) and treatment for 3 weeks with either vehicle, dexamethasone, obatoclax, or the combination. P < 0.02 for dexamethasone and obatoclax versus vehicle, dexamethasone, or obatoclax alone for both xenograft experiments.