ABSTRACT
Hypoxia inducible factor-1 (HIF-1) directs the cellular response to low oxygen and plays a key role in tumour survival and growth. Here we use an inhibitor of the HIF-1α/HIF-1ß protein-protein interaction to show the presence of an epigenetically controlled transactivation loop whereby the HIF-1 transcription factor promotes the expression of its own α-subunit in hypoxic cancer cells.
Subject(s)
Epigenesis, Genetic , Gene Expression Regulation , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1/metabolism , Transcriptional Activation , Cell Line , Humans , Hypoxia/genetics , Hypoxia/metabolism , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
