Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib
AU - Liu, F.-T.
AU - Agrawal, S.G.
AU - Movasaghi, Z.
AU - Wyatt, P.B.
AU - Rehman, I.U.
AU - Gribben, J.G.
AU - Newland, A.C.
AU - Jia, L.
PY - 2008
Y1 - 2008
N2 - Dietary flavonolds have many health-promoting actions, including anticancer activity via proteasome inhibition. Bortezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but Is not effective In chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive In vitro to bortezomlb-induced apoptosis when cultured in medium, the killing activity was blocked when cultured In 50% fresh autologous plasma. Dietary flavonoids, quercetin and myrocetin, which are abundant In plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH) 2 , in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution Is required when giving dietary advice to patients. © 2008 by The American Society of Hematology.
AB - Dietary flavonolds have many health-promoting actions, including anticancer activity via proteasome inhibition. Bortezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but Is not effective In chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive In vitro to bortezomlb-induced apoptosis when cultured in medium, the killing activity was blocked when cultured In 50% fresh autologous plasma. Dietary flavonoids, quercetin and myrocetin, which are abundant In plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH) 2 , in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution Is required when giving dietary advice to patients. © 2008 by The American Society of Hematology.
KW - acetylcysteine
KW - apigenin
KW - benzyloxycarbonylleucylleucylleucinal
KW - boric acid
KW - bortezomib
KW - caspase 3
KW - caspase 8
KW - caspase 9
KW - curcumin
KW - cytochrome c
KW - delphinidin
KW - epigallocatechin
KW - epigallocatechin gallate
KW - flavonoid
KW - functional group
KW - kaempferol
KW - mg 262
KW - myricetin
KW - protein Bax
KW - quercetin
KW - reactive oxygen metabolite
KW - resveratrol
KW - unclassified drug
KW - antineoplastic agent
KW - BAX protein, human
KW - boronic acid derivative
KW - proteinase inhibitor
KW - pyrazine derivative
KW - scavenger
KW - antineoplastic activity
KW - antioxidant activity
KW - apoptosis
KW - article
KW - B lymphocyte
KW - cell death
KW - chemical reaction
KW - chronic lymphatic leukemia
KW - concentration response
KW - controlled study
KW - diet supplementation
KW - drug blood level
KW - drug effect
KW - drug efficacy
KW - drug inhibition
KW - drug structure
KW - enzyme activity
KW - human
KW - human cell
KW - IC 50
KW - myeloma cell
KW - plasma
KW - priority journal
KW - protein secretion
KW - upregulation
KW - B cell leukemia
KW - B cell lymphoma
KW - cell line
KW - diet
KW - diet therapy
KW - drug antagonism
KW - in vitro study
KW - metabolism
KW - multiple myeloma
KW - pathology
KW - tumor cell line
KW - Antineoplastic Agents
KW - Apoptosis
KW - bcl-2-Associated X Protein
KW - Boric Acids
KW - Boronic Acids
KW - Cell Line, Transformed
KW - Cell Line, Tumor
KW - Cytochromes c
KW - Diet
KW - Flavonoids
KW - Free Radical Scavengers
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Lymphoma, B-Cell
KW - Multiple Myeloma
KW - Protease Inhibitors
KW - Pyrazines
KW - Quercetin
U2 - 10.1182/blood-2008-04-150227
DO - 10.1182/blood-2008-04-150227
M3 - Journal article
VL - 112
SP - 3835
EP - 3846
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -