title: Drug activity screening based on microsomes-hydrogel system in predicting metabolism induced antitumor effect of oroxylin A.
abstract: A novel microsomes-hydrogel added cell culture system (MHCCS) was employed in the antitumor activity screening of natural compounds, aiming to achieve drug screening with better in vivo correlation, higher initiative to explore the potential active metabolites, and investigation of the antitumor mechanism from the perspective of metabolism. MTT assay and cell apoptosis detection showed that test drug oroxylin A (OA) had enhanced cytotoxicity and wogonin (W) with reduced cytotoxicity on MCF-7 cell line upon MHCCS incubation. In vivo antitumor evaluations also demonstrated that OA induced higher tumor inhibition than W at the same dosage. To explore the reasons, nine major metabolites of OA were separated and collected through UPLC-Q-TOF and semi-preparative HPLC. Metabolites M318 exhibited higher cytotoxicity than OA and other metabolites by MTT assay. (1)H NMR spectrums, HPLC and TOF MS/MS results revealed that OA was catalyzed into its active metabolite M318 via a ring-opening reaction. M318 induced significant cell apoptosis and S-phase arrest through affecting tumor survival related genes after mechanism study. In conclusion, our MHCCS could be a useful tool for drug activity screening from a perspective of metabolism.
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medical Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Tong
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003470:Culture Media; D005419:Flavonoids; D020100:Hydrogels; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one