ROS induction and ATR inhibition synergize in inducing multiple myeloma (MM) cell death. ROS induction and ATR inhibition synergize in inducing multiple.

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ROS induction and ATR inhibition synergize in inducing multiple myeloma (MM) cell death. ROS induction and ATR inhibition synergize in inducing multiple myeloma (MM) cell death. A, H929 multiple myeloma cells (left) and OPM-2 multiple myeloma cells (right) were transiently transfected with ATR shRNAs or scrambled shRNAs and incubated with DMSO or 1 μmol/L PL starting from day 0 of transfection. Cell growth by cell counting with trypan blue exclusion was performed in triplicate. B, apoptosis by Annexin V–PI staining was evaluated in the same conditions as A at 48 hours from transfection. Summary of two independent experiments is shown. C, combination studies by MTT viability assay using 0.5 to 1.5 μmol/L VE-821 and 1 to 1.5 μmol/L PL were performed in H929 and OPM-2 cells after 48-hour treatment. CI plot with CI values are shown as insets. D, combination studies by MTT viability assay in multiple myeloma patient cells as in C. E, combination studies by MTT viability assay using 50 to 300 nmol/L PL, 1.25 to 2.5 nmol/L bortezomib (BTZ), and 2.5 to 5 nmol/L carfilzomib (CFZ) in H929 and 1 representative patient. CI plot with CI values are shown as insets. F, schematic model. Top, oncogene activation (as for example MYC) increases replicative stress and ROS, thus triggering DNA damage in multiple myeloma cells that is maintained below a critical threshold by ATR-mediated resolution of DNA-replicative stress and increase of enzymes reducing ROS levels. Bottom, combined inhibition of ATR (stress sensitization) and increase in ROS (stress overload) elicits an increase in unresolved DNA damage that leads to apoptosis. **, P < 0.001 (Student t test). Francesca Cottini et al. Cancer Discovery 2015;5:972-987 ©2015 by American Association for Cancer Research