Regulation of apoptosis by modified naringenin derivatives in human colorectal carcinoma RKO cells.
Flavonoids are micronutrients that are widely detected in foods of plant origin and have been ascribed pharmacological properties. Several biological functions of flavonoids have been thus far identified, whereas there currently exists a lack of evidence to support the relationship between the structure-activity relationship and apoptosis-inducing activity. In an attempt to determine the importance of the OH group or substitution of the 5- or 7-carbon in the diphenylpropane skeleton of flavonoids, we selected 14 different flavonoids with different structures, particularly with regard to the 5- or 7-carbon, and found that naringenin treatment caused a slight decrease in the cell viability of the human colorectal carcinoma RKO cells. Next, in order to characterize the effects of specific substitutions of the 7-carbon of naringenin on apoptosis-regulatory activities, and in an attempt to develop anti-proliferative flavonoid derivatives that would be more effective against colon cancer, we originally synthesized several modified naringenin derivatives (MNDs) including 7-O-benzyl naringenin (KUF-1) and 7-O-(m-metoxybenzyl) naringenin (KUF-2). Treatment with KUF-1 or KUF-2 resulted in significant apoptosis-inducing effects concomitant with losses in mitochondrial membrane potential, caspase activation, intracellular ROS production, and sustained ERK activation. Our data show that KUF-1 or KUF-2 regulate the apoptosis of RKO cells via intracellular ROS production coupled with the concomitant activation of the ERK signaling pathway, thereby implying that hydroxylation or substitution at C7 is critical for the apoptosis-inducing activity of flavonoids.
Lee
Eung-Ryoung
ER
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, South Korea.
Kang
Yong-Jin
YJ
Kim
Hyun-Jeong
HJ
Choi
Hye-Yeon
HY
Kang
Geun-Ho
GH
Kim
Jung-Hyun
JH
Kim
Bong-Woo
BW
Jeong
Hyo-Soon
HS
Park
Yong-Sun
YS
Cho
Ssang-Goo
SG
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases; D044950:Flavanones / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship
D044950:Flavanones; D005419:Flavonoids; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; C005273:naringenin