Naringenin-induced apoptosis is attenuated by Bcl-2 but restored by the small molecule Bcl-2 inhibitor, HA 14-1, in human leukemia U937 cells.
Naringenin, a naturally occurring citrus flavonone, has shown cytotoxicity in various human cancer cell lines as well as inhibitory effects on tumor growth and there is increasing interest in its therapeutic applications. In this study, the effect of ectopic Bcl-2 expression on naringenin-induced apoptosis was investigated. We found that Bcl-2 overexpression markedly protected human leukemia U937 cells from time- and dose-dependent induction of apoptosis by naringenin, as did caspase-3 and caspase-9 inhibitors. Additionally, Bcl-2 overexpression attenuated naringenin-induced Bax translocation and cytosolic release of cytochrome c. Our results also indicated that co-administration of HA14-1 and naringenin increased apoptosis in Bcl-2 overexpressing U937 cells by restoring mitochondrial dysfunction and activation of caspase-9 and caspase-3, as well as by cleavage of poly (ADP-ribose) polymerase. Taken together, these observations indicate that Bcl-2 confers apoptosis resistance to naringenin by inhibiting a mitochondrial amplification step in U937 cells.
Jin
Cheng-Yun
CY
Department of Biomaterial Control (BK21 program), Dongeui University Graduate School, Yangjung-dong San 45, Busanjin-gu, Busan 614-052, South Korea.
Park
Cheol
C
Lee
Jun-Hyuk
JH
Chung
Kyung Tae
KT
Kwon
Taeg Kyu
TK
Kim
Gi-Young
GY
Choi
Byung Tae
BT
Choi
Yung Hyun
YH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D001578:Benzopyrans; D061945:Caspase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D044950:Flavanones; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D045304:Cytochromes c; C005273:naringenin