title: Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from Cinnamomi Cortex extract.
abstract: Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor because Nrf2-regulated enzymes play a key role in antioxidant and detoxification processes. Recent studies have reported that lung cancer cells overexpressing Nrf2 exhibit increased resistance to chemotherapy. Suppression of overexpressed Nrf2 is needed for a new therapeutic approach against lung cancers. In the present study, we found that Cinnamomi Cortex extract (CCE) has an ability to suppress Nrf2-regulated enzyme activity and Nrf2 expression in human lung cancer A549 cells with high Nrf2 activity. Moreover, we demonstrated that CCE significantly enhances sensitivity of A549 cells to the cytotoxic action of doxorubicin and etoposide as well as increasing the intracellular accumulation of both drugs. These results suggest that CCE might be an effective concomitant agent to reduce anticancer drug resistance derived from Nrf2 overexpression. Bioactivity-guided fractionation revealed that procyanidin tetramers and pentamers contained in CCE were active components in suppressing Nrf2.
authors.affiliation: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohnuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Ayano
authors.initials: A
authors.lastname: Itoi
authors.forename: Ayako
authors.initials: A
authors.lastname: Kawana
authors.forename: Takahito
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ogura
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratsuka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002935:Cinnamomum zeylanicum; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044945:Proanthocyanidins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D051267:NF-E2-Related Factor 2; D044945:Proanthocyanidins; C532132:cinnamomi cortex; D005047:Etoposide; D004317:Doxorubicin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human