Natural polyphenols antagonize the antimyeloma activity of proteasome inhibitor bortezomib by direct chemical interaction.
Bortezomib is a therapeutic proteasome inhibitor with antimyeloma activity and polyphenols are well known compounds that exert antiproliferative effects against tumuors. We attempted to co-treat myeloma cells with bortezomib and polyphenols, anticipating a synergistic effect. However, the anticancer activity of bortezomib was blocked by the polyphenols. The structural features of the polyphenols correlated strikingly with their antagonistic effect; in particular, the presence or absence of a vicinal diol moiety was the key element for effective blockage of the anticancer function of bortezomib. We speculated that the vicinal diols in the polyphenols interact with the boronic acid of bortezomib and convert the active triangular boronic acid of bortezomib to an inactive tetrahedral boronate, thus abolishing the antimyeloma activity of bortezomib. We confirmed this hypothesis by (11)B nuclear magnetic resonance spectroscopy and an in vitro assay on multiple myeloma (MM) cell lines and primary myeloma cells from patients. Based on these findings, restriction of the intake of natural polyphenols in foods or vitamin supplements during bortezomib treatment in MM patients should be considered.
Kim
Tae Young
TY
Department of Molecular and Clinical Oncology, Seoul National University College of Medicine, Seoul, Korea.
Park
Jongmin
J
Oh
Bora
B
Min
Hyun Jung
HJ
Jeong
Tae-Sook
TS
Lee
Jae Hoon
JH
Suh
Cheolwon
C
Cheong
June-Won
JW
Kim
Hyo Jung
HJ
Yoon
Sung-Soo
SS
Park
Seung Bum
SB
Lee
Dong Soon
DS
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000037:antagonists & inhibitors*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000178:diet therapy*; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D011719:Pyrazines / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D011719:Pyrazines; D000069286:Bortezomib