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.

Genetic Landscape of Electron Transport Chain Complex I Dependency in Acute Myeloid Leukemia

“…So as to investigate whether Mubritinib indeed behaves as an ETC inhibitor in AML cells, we compared the inhibition pattern induced by Mubritinib treatment with that of known ETC inhibitors (Deguelin (complex I), 47,48 and Oligomycin (complex V)) for 56 primary AML samples (see patient characteristics in Supplementary Table S7). We found that the two ETC inhibitors’ inhibitory patterns are highly similar to that of Mubritinib (r=0.9, p<0.0001 for Deguelin, Fig.…”

Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations

“…In Guadeloupe (French West Indies) there is an unusually high incidence of atypical parkinsonism, which has been linked to regular consumption of these plants, in particular soursop (Lannuzel et al, 2003(Lannuzel et al, , 2007(Lannuzel et al, , 2008. The thiophene-3-carboxamide analog of annonaceous acetogenins JCI-20679 inhibited the oxygen consumption of human non-small cell lung carcinoma NCI-H23 cells with a half maximal inhibitory concentration (IC 50 ) of 170 nM (Akatsuka et al, 2016). The acetogenin bullatacin, or rolliniastatin-2, inhibits respiration in insect-derived Sf9 cells.…”

APTM, a Thiophene Heterocyclic Compound, Inhibits Human Colon Cancer HCT116 Cell Proliferation Through p53-Dependent Induction of Apoptosis

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