Interactive effects of polymethoxy flavones from Citrus on cell growth inhibition in human neuroblastoma SH-SY5Y cells

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• 作者：Yukihiro Akao ; Tomohiro itoh ; Kenji Ohguchi ; Munekazu Iinuma ; Yoshinori Nozawa
• 关键词：Growth inhibition ; Synergistic effect ; Polymethoxy flavones ; Apoptosis ; Citrus
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：15 March 2008
• 年：2008
• 卷：16
• 期：6
• 页码：2803-2810
• 全文大小：845 K

文摘

Much evidence indicates that typical phytochemicals such as resveratrol, epigallocatechin gallate, and curcumin have a growth inhibitory effect against cancer cells when each is tested separately. However, when fruits and vegetables including a mixture of phytochemicals are consumed, it is unclear whether this anti-proliferative activity is elicited in the body. Initially, we found that nobiletin, a typical polymethoxy flavone from Citrus, had a preventive effect on H₂O₂-induced apoptosis at 20–30 μM in human neuroblastoma SH-SY5Y cells. Nobiletin acted as a signal modulator to attenuate the activation of the intrinsic pathway of the apoptosis induced by H₂O₂ exposure. On the other hand, tangeretin and 5-demethyl nobiletin, which are also polymethoxy flavones from Citrus, were shown to have a growth inhibitory effect by us and others. These results led us to investigate the interactive effects of these polymethoxy flavones on cell growth. In the present study, we found that tangeretin, nobiletin, and 5-demethyl nobiletin exhibited a cancelling, synergistic, or additive effect when combinations of two of these three compounds were tested. As to the structure–activity relationship, the methyl group at C-5 in nobiletin was shown to contribute to the anti-proliferative effect. By the combined treatment with tangeretin and 5-demethyl nobiletin, the apoptotic cell population and the activity of caspase-3 were synergistically elevated. The finding that tangeretin and 5-demethyl nobiletin induced apoptosis by reducing the mitochondrial membrane potential suggested that an intrinsic pathway of apoptosis was synergistically activated by the combination treatment with tangeretin and 5-demethyl nobiletin. On the other hand, in the combined treatment including nobiletin, the growth inhibitory activity of tangeretin was reduced. These results indicate the relevance of the combination of phytochemicals for the enhancement of the anticancer effect.