Bortezomib interactions with chemotherapy agents in acute leukemia in vitro

Abstract

Although there is effective chemotherapy for many patients with leukemia, 20% of children and up to 65% of adults relapse. Novel therapies are needed to treat these patients. Leukemia cells are very sensitive to the proteasome inhibitor bortezomib (VELCADE(R), PS-341), which enhances the in vitro cytotoxic effects of dexamethasone and doxorubicin in multiple myeloma. To determine if bortezomib enhances the cytotoxicity of agents used in leukemia, we employed an in vitro tetrazolium-based colorimetric assay (MTT) to evaluate the cytotoxic effects of bortezomib alone and in combination with dexamethasone, vincristine, doxorubicin, cytarabine, asparaginase, geldanamycin, trichostatin A, and the bcl-2 inhibitor HA14.1. We demonstrated that primary leukemia lymphoblasts and leukemia cell lines are sensitive to bortezomib, with an average IC(50) of 12 nM. Qualitative and quantitative bortezomib-drug interactions were evaluated using the universal response surface approach (URSA). Bortezomib was synergistic with dexamethasone in dexamethasone-sensitive leukemia cells, and additive with vincristine, asparaginase, cytarabine, and doxorubicin. The anti-leukemic activity of bortezomib was also additive with geldanamycin and HA14.1, and additive or synergistic with trichostatin A. These results were compared to analysis using the median-dose effect method, which generated complex drug interactions due to differences in dose-response curve sigmoidicities. These data suggest bortezomib could potentiate the cytotoxic effects of combination chemotherapy in patients with leukemia.

The proteasome inhibitors bortezomib and PR‐171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells

“…When comparing low/intermediate drug concentrations a further decrease in both viability and proliferation was observed compared to cultures containing each of the drugs alone. Recent studies have described both agonistic and antagonistic effects on leukaemic cell lines and limited numbers of primary cells when combining standard antileukaemic chemotherapeutic drugs and proteasome inhibitors (Horton et al, 2006;Minderman et al, 2006). Our present results showed no evidence for antagonistic, but obvious additive effects on unselected primary AML cells.…”

Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma

“…The reversal of CAM-DR by bortezomib may underlie its broad range of synergy with other anticancer drugs as recently described (Horton et al, 2006;Noborio-Hatano et al, 2007). Unfortunately, severe pulmonary complications have been reported in Japanese patients treated with bortezomib (Miyakoshi et al, 2006).…”

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

“…228 All these studies have validated NF-kB as a promising therapeutic target downstream of PI3K/Akt in AML. It may also be worth mentioning here that bortezomib, an indirect NF-kB inhibitor which targets the proteasome, 229 has been approved for treatment of multiple myeloma 230 and is currently under clinical evaluation for other hematological malignancies, including AML. 231 Interestingly, bortezomib induced apoptosis of bone marrow monuclear myeloid (BMMM) cells from patients with high-risk MDS, a preneoplastic condition which frequently develops into overt AML, and is characterized by a progressive increase in bone marrow blasts with reduced apoptotic capacities.…”