Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells.
Hydroxylated polymethoxyflavones (PMFs) are a class of novel flavonoid compounds mainly found in citrus plants. We studied the effects of three major 5-hydroxy PMFs, namely: 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone, and 5-hydroxy-6,7,8,4'-tetramethoxyflavone, on human colon cancer HCT116 and HT29 cells. Their effects were compared with those produced by their permethoxylated counterparts, namely: nobiletin, 3,5,6,7,8,3',4'-heptamethoxylflavone, and tangeretin. 5-Hydroxy PMFs showed much stronger inhibitory effects on the growth of the colon cancer cells in comparison with their permethoxylated counterparts, suggesting the pivotal role of hydroxyl group at 5-position in the enhanced inhibitory activity by 5-hydroxy PMFs. Flow cytometry analysis demonstrated that three 5-hydroxy PMFs produced different effects on the cell cycle and apoptosis, which may suggest that three 5-hydroxy PMFs act through different mechanisms. For example, 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone caused cell cycle arrest at G2/M phase in HT29 cells, while 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone led to significant G0/G1 phase arrest. In contrast, 5-hydroxy-6,7,8,4'-tetramethoxyflavone increased sub-G0/G1 cell population, which has been confirmed to be due to enhanced apoptosis. Our results further demonstrated that the inhibitory effects of 5-hydroxy PMFs were associated with their ability in modulating key signaling proteins related to cell proliferation and apoptosis, such as p21(Cip1/Waf1), CDK-2, CDK-4, phosphor-Rb, Mcl-1, caspases 3 and 8, and poly ADP ribose polymerase (PARP).
Qiu
Peiju
P
Marine Drug and Food Institute, Ocean University of China, Qingdao Shandong, P R China.
Dong
Ping
P
Guan
Huashi
H
Li
Shiming
S
Ho
Chi-Tang
CT
Pan
Min-Hsiung
MH
McClements
David Julian
DJ
Xiao
Hang
H
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009336:Necrosis; D014176:Protein Biosynthesis / Q000187:drug effects; D013329:Structure-Activity Relationship
C553978:5-hydroxy-6,7,8,3',4'-pentamethoxyflavone; C553979:5-hydroxy-6,7,8,4'-tetramethoxyflavone; D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; C521815:5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone