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Zooecdysteroids (arthropod steroid hormones) regulate the development of arthropods and probably many other invertebrates. Phytoecdysteroids are analogues occurring in a wide range of plant species, where they contribute to the deterrence of phytophagous invertebrates. The purpose of this short review is to summarise findings on the occurrence, metabolism and pharmacological effects of ecdysteroids in mammalian systems and to draw attention to their potential applications, particularly in gene-switch technology, where ecdysteroid analogues (steroidal and non-steroidal) can be used as effective and potent elicitors.

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Ecdysteroids are widely used as inducers for gene-switch systems based on insect ecdysteroid receptors and genes of interest placed under the control of ecdysteroid-response elements. We review here these systems, which are currently mainly used in vitro with cultured cells in order to analyse the role of a wide array of genes, but which are expected to represent the basis for future gene therapy strategies. Such developments raise several questions, which are addressed in detail.First, the metabolic fate of ecdysteroids in mammals, including humans, is only poorly known, and the rapid catabolism of ecdysteroids may impede their use as in vivo inducers.A second set of questions arose in fact much earlier with the pioneering “heterophylic” studies of Burdette in the early sixties on the pharmacological effects of ecdysteroids on mammals. These and subsequent studies showed a wide range of effects, most of them being beneficial for the organism (e.g. hypoglycaemic, hypocholesterolaemic, anabolic). These effects are reviewed and critically analysed, and some hypotheses are proposed to explain the putative mechanisms involved.All of these pharmacological effects have led to the development of a wide array of ecdysteroid-containing preparations, which are primarily used for their anabolic and/or “adaptogenic” properties on humans (or horses or dogs). In the same way, increasing numbers of patents have been deposited concerning various beneficial effects of ecdysteroids in many medical or cosmetic domains, which make ecdysteroids very attractive candidates for several practical uses.It may be questioned whether all these pharmacological actions are compatible with the development of ecdysteroid-inducible gene switches for gene therapy, and also if ecdysteroids should be classified among doping substances.20E20-hydroxyecdysone2d20E2-deoxy-20-hydroxyecdysone2dE2-deoxyecdysoneBAHbisacylhydrazineBmEcRBombyx mori EcRCfEcRChoristoneura fumiferana EcRCfUSPChoristoneura fumiferana USPCHOChinese hamster ovaryCMVcytomegalovirusDBDDNA-binding domainDmEcRDrosophila melanogaster EcRAbbEecdysoneEcRecdysteroid receptorEcREecdysteroid response elementEHTeffective half-timeEREoestrogen response elementGRglucocorticoid receptorGREglucocorticoid response elementHEKhuman embryonic kidneyHvEcRHeliothis virescens EcRLBDligand binding domainmurAmuristerone APKAprotein kinase ApolBpolypodine BponAponasterone APPARperoxisome proliferator-activated receptorRARretinoic acid receptorRXRretinoid X receptorTRthyroid receptorUSPultraspiracleVDRvitamin D receptorVEGFvascular endothelial growth factor

Phytoecdysteroids are analogues of arthropod steroid hormones found in plants, where they deter predation by non-adapted predators. There is potential to exploit this to develop new strategies for pest control, either by using ecdysteroids as lead molecules for the design of novel pest control agents or by alteration of ecdysteroid levels/profiles in crop plants through plant breeding or genetic modification. However, it is other properties of phytoecdysteroids that have led to a rapid recent increase in scientific and commercial interest in these molecules. They are apparently non-toxic to mammals and a wide range of beneficial pharmacological (adaptogenic, anabolic, anti-diabetic, hepatoprotective, immunoprotective, wound-healing, and perhaps even anti-tumour) activities is claimed for them. In particular, this has led to a large (and unregulated) market for ecdysteroid-containing preparations for body-builders, sportsmen, and pets, among others. Ecdysteroids are also being considered as nutraceutical additives to food products. Further, ecdysteroids are good candidates as elicitors for gene-switch systems to be used in medical gene therapy and research applications. In this article, I review the applications of phytoecdysteroids and assess their future potential.

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Two triterpenoids, cucurbitacins B and D, have been isolated from seeds of Iberis umbellata (Cruciferae) and shown to be responsible for the antagonistic activity of a methanolic extract of this species in preventing the 20-hydroxyecdysone (20E)-induced morphological changes in the Drosophila melanogaster BII permanent cell line. With a 20E concentration of 50 nM, cucurbitacins B and D give 50% responses at 1.5 and 10 microM respectively. Both cucurbitacins are able to displace specifically bound radiolabelled 25-deoxy-20-hydroxyecdysone (ponasterone A) from a cell-free preparation of the BII cells containing ecdysteroid receptors. The Kd values for cucurbitacins B and D (5 and 50 microM respectively) are similar to the concentrations required to antagonize 20E activity with whole cells. Cucurbitacin B (cucB) prevents stimulation by 20E of an ecdysteroid-responsive reporter gene in a transfection assay. CucB also prevents the formation of the Drosophila ecdysteroid receptor/Ultraspiracle/20E complex with the hsp27 ecdysteroid response element as demonstrated by gel-shift assay. This is therefore the first definitive evidence for the existence of antagonists acting at the ecdysteroid receptor. Preliminary structure/activity studies indicate the importance of the Delta23-22-oxo functional grouping in the side chain for antagonistic activity. Hexanorcucurbitacin D, which lacks carbon atoms C-22 to C-27, is found to be a weak agonist rather than an antagonist. Moreover, the side chain analogue 5-methylhex-3-en-2-one possesses weak antagonistic activity.

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