Proteasome inhibitor bortezomib induces apoptosis in prednisone-resistant childhood acute lymphoblastic leukemia cells

Abstract

The response to initial glucocorticoid (gc) therapy in childhood acute lymphoblastic leukemia (ALL) reliably predicts the response to multi-agent chemotherapy. We detected members of the ubiquitin proteasome system (UPS) to be altered in gc resistant leukemic cell lines, suggesting that the associated pathways might be involved in multi-agent chemotherapy resistance in childhood ALL. To investigate whether the proteasome inhibitor bortezomib (VELCADE®) acts synergistically with gc treatment, human B-cell precursor leukemic cell lines, prednisone poor responding MHH cALL 2 (PPR) and prednisone good responding MHH cALL 3 (PGR), were treated with prednisolone and various concentrations of bortezomib. Viability-, apoptosis- and necrosis-rates were determined. Both cell lines showed a dose-dependent increase in caspase activity after bortezomib single treatment. But only PGR cells showed an additive effect after combined treatment with both drugs, compared to prednisolone. In contrast, both cell lines showed decreased viability and elevated PI positivity. Western blot analysis of Poly-(ADP-ribose)-polymerase-1 suggested that combined treatment strongly promoted necrotic cleavage of this protein in PPR cells. To conclude, proteasome inhibitors like bortezomib seem to sensitize gc-resistant childhood ALL cells for prednisone treatment.