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Cancer Chemotherapy and Pharmacology

Published in:

01-07-2007 | Original Article

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status

Authors: Hans Minderman, Yunfei Zhou, Kieran L. O’Loughlin, Maria R. Baer

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2007

Abstract

Purpose

The proteasome inhibitor bortezomib may be effective in combination with cytarabine and anthracyclines in the treatment of acute myeloid leukemia (AML) by virtue of targeting aberrantly activated NF-κB in AML stem cells. We tested whether bortezomib cytotoxicity is affected by multidrug resistance (MDR) proteins expressed in AML cells. We also tested whether bortezomib interactions with cytarabine and anthracyclines are affected by p53, because proteasome inhibition stabilizes p53 and may thus cause cell cycle arrest.

Experimental design

Bortezomib sensitivity of cell lines overexpressing P-glycoprotein, multidrug resistance protein-1, breast cancer resistance protein and lung resistance protein was studied in the presence and absence of established modulators of these transport proteins. Drug interactions during simultaneous and sequential exposure to bortezomib and anthracyclines or cytarabine in diverse ratios were evaluated by isobologram and combination index analyses in AML cell lines with wild type and inactive p53 and were correlated with cell cycle perturbations induced by bortezomib.

Results

Of the MDR mechanisms studied, only P-glycoprotein conferred resistance to bortezomib, and resistance was only twofold. Interactions between bortezomib and anthracylines and cytarabine changed from antagonistic to additive or synergistic with increasing drug activity levels and were not affected by p53 status.

Conclusions

MDR proteins and p53 do not affect bortezomib cytotoxicity or in vitro interactions with anthracyclines or cytarabine, but these interactions are concentration-dependent, and this concentration-dependency should be considered in the design of combination regimens.

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Title: Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status
Authors: Hans Minderman
Yunfei Zhou
Kieran L. O’Loughlin
Maria R. Baer
Publication date: 01-07-2007
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2007
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-006-0367-6

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Abstract

Purpose

Experimental design

Results

Conclusions

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