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


METHODS
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.
Minderman
Hans
H
Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. hans.minderman@roswellpark.org
Zhou
Yunfei
Y
O'Loughlin
Kieran L
KL
Baer
Maria R
MR
D018943:Anthracyclines / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018943:Anthracyclines; D000964:Antimetabolites, Antineoplastic; D001897:Boronic Acids; D000069286:Bortezomib; D003561:Cytarabine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53