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Monodemethylated polymethoxyflavones from sweet orange ( Citrus sinensis ) peel Inhibit growth of human lung cancer cells by apoptosis
Author(s) -
Xiao Hang,
Yang Chung S.,
Li Shiming,
Jin Huanyu,
Ho ChiTang,
Patel Trusha
Publication year - 2009
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.200800057
Subject(s) - nobiletin , apoptosis , citrus × sinensis , cell cycle , orange (colour) , apigenin , cancer cell , biology , growth inhibition , cell growth , lung cancer , flavones , citrus unshiu , chemistry , biochemistry , botany , cancer , flavonoid , food science , medicine , genetics , antioxidant
Polymethoxyflavones (PMFs) are almost exclusively found in the Citrus genus, particularly in the peels of sweet orange ( Citrus sinensis L. Osbeck) and mandarin ( C. reticulate Blanco). We studied the effects of two major PMFs, namely, nobiletin and 3,5,6,7,8,3′,4′‐heptamethoxyflavone (HMF), and two major monodemethylated PMFs, namely 5‐hydroxy‐3,7,8,3′,4′‐pentamethoxyflavone (5HPMF), and 5‐hydroxy‐3,6,7,8,3′,4′‐hexamethoxyflavone (5HHMF), on the growth of human lung cancer H1299, H441, and H460 cells. Monodemethylated PMFs were much more potent in growth inhibition of lung cancer cells than their permethoxylated counterpart PMFs. In H1299 cells, cell cycle analyses further revealed that monodemethylated PMFs caused significant increase in sub‐G0/G1 phase, suggesting possible role of apoptosis in the growth inhibition observed, whereas the permethoxylated counterpart PMFs did not affect cell cycle distribution at same concentrations tested. These results strongly suggested that the phenolic group is essential for the growth inhibitory activity of monodemethylated PMFs. Further studies in H1299 cells demonstrated that monodemethylated PMFs downregulated oncogenic proteins, such as iNOS, COX‐2, Mcl‐1, and K‐ras, as well as induced apoptosis evidenced by activation of caspase‐3 and cleavage of PARP. Our results provide rationale to develop orange peel extract enriched with monodemethylated PMFs into value‐added nutraceutical products for cancer prevention.