title: A novel thiophene-3-carboxamide analog of annonaceous acetogenin exhibits antitumor activity via inhibition of mitochondrial complex I.
abstract: Previously we synthesized JCI-20679, a novel thiophene-3-carboxamide analog of annonaceous acetogenins which have shown potent antitumor activity, with no serious side effects, in mouse xenograft models. In this study, we investigated the antitumor mechanism of JCI-20679. The growth inhibition profile (termed "fingerprint") of this agent across a panel of 39 human cancer cell lines (termed "JFCR39") was measured; this fingerprint was analyzed by the COMPARE algorithm utilizing the entire drug sensitivity database for the JFCR39 panel. The JCI-20679-specific fingerprint exhibited a high similarity to those of two antidiabetic biguanides and a natural rotenoid deguelin which were already known to be mitochondrial complex I inhibitors. In addition, the fingerprint exhibited by JCI-20679 was not similar to that displayed by any typical anticancer drugs within the database, suggesting that it has a unique mode of action. In vitro experiments using bovine heart-derived mitochondria showed direct inhibition of mitochondrial complex I by JCI-20679 and associated derivatives. This inhibition of enzymatic activity positively correlated with tumor cell growth inhibition. Furthermore, a fluorescently labeled derivative of JCI-20679 localized to the mitochondria of live cancer cells in vitro. These results suggest that JCI-20679 can inhibit cancer cell growth by inhibiting mitochondrial complex I. Our results show that JCI-20679 is a novel anticancer drug lead with a unique mode of action.
authors.affiliation: Molecular Pharmacology Cancer Chemotherapy Center Japanese Foundation for Cancer Research Tokyo Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Akatsuka
authors.affiliation: Pharmaceutical Manufacturing Chemistry Kyoto Pharmaceutical University Kyoto Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kojima
authors.affiliation: Molecular Pharmacology Cancer Chemotherapy Center Japanese Foundation for Cancer Research Tokyo Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Okamura
authors.affiliation: Molecular Pharmacology Cancer Chemotherapy Center Japanese Foundation for Cancer Research Tokyo Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.affiliation: Molecular Pharmacology Cancer Chemotherapy Center Japanese Foundation for Cancer Research Tokyo Japan; Present address: Pharmaceutical and Medical Devices Agency Tokyo Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
keywords: Antitumor compound; COMPARE analysis; complex I; mitochondria; natural polyketide