title: The Hydroxyl at Position C1 of Genipin Is the Active Inhibitory Group that Affects Mitochondrial Uncoupling Protein 2 in Panc-1 Cells.
abstract: Genipin (GNP) effectively inhibits uncoupling protein 2 (UCP2), which regulates the leakage of protons across the inner mitochondrial membrane. UCP2 inhibition may induce pancreatic adenocarcinoma cell death by increasing reactive oxygen species (ROS) levels. In this study, the hydroxyls at positions C10 (10-OH) and C1 (1-OH) of GNP were hypothesized to be the active groups that cause these inhibitory effects. Four GNP derivatives in which the hydroxyl at position C10 or C1 was replaced with other chemical groups were synthesized and isolated. Differences in the inhibitory effects of GNP and its four derivatives on pancreatic carcinoma cell (Panc-1) proliferation were assessed. The effects of GNP and its derivatives on apoptosis, UCP2 inhibition and ROS production were also studied to explore the relationship between GNP's activity and its structure. The derivatives with 1-OH substitutions, geniposide (1-GNP1) and 1-ethyl-genipin (1-GNP2) lacked cytotoxic effects, while the other derivatives that retained 1-OH, 10-piv-genipin (10-GNP1) and 10-acetic acid-genipin (10-GNP2) exerted biological effects similar to those of GNP, even in the absence of 10-OH. Thus, 1-OH is the key functional group in the structure of GNP that is responsible for GNP's apoptotic effects. These cytotoxic effects involve the induction of Panc-1 cell apoptosis through UCP2 inhibition and subsequent ROS production.
authors.affiliation: Laboratory of Immunology and Virology, Experiment Center For Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Immunology and Virology, Experiment Center For Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hou
authors.affiliation: Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Immunology and Virology, Experiment Center For Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Innovation of Traditional Chinese Medicine Laboratory, College of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Fu
authors.affiliation: Laboratory of Immunology and Virology, Experiment Center For Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Cai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D039823:Iridoids / Q000737:chemistry* / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D039823:Iridoids; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; C007834:genipin