Tailor-Made Fluorescent Trilobolide To Study Its Biological Relevance

Abstract

Trilobolide (Tb) is a potent natural counterpart of thapsigargin, which has shown promising results in cancer clinical trials. Here, we report a rational approach to study intracellular localization and biological activity of this sesquiterpene lactone. We conjugated Tb with a green-emitting Bodipy dye attached by alternative linkers of different lengths. The live-cell imaging of the prepared bioconjugates brought clear evidence that Tb-Bodipy localized in the endoplasmic reticulum (ER) of various cancer cell lines. The localization signal was compared with ER-specific dyes. Cytotoxicity of Tb conjugates and impact on the mitochondrial physiology and nitric oxide release were also studied. The nitric oxide production and cytokine secretion in rat peritoneal cells indicate immunobiological potential of these lactone bioconjugates. In summary, our Tb-Bodipy conjugates could help us to reveal the molecular mechanism of trilobolide for its further potential use in biomedical applications.

Archangelolide: Sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

“…First, we analyzed the rate of cell uptake of compound 5 in U-2 OS ( which is in agreement with the site of localization of another SL, a SERCA inhibitor, trilobolide [3]. However, we observed partial co-localization also in mitochondria, in which SERCA is not present.…”

“…Trilobolide exhibits strong induction of nitric oxide (NO) in eukaryotic cells, which in turn evokes synthesis of IL-6, INF-γ and TNF-α. Furthermore, trilobolide has very similar structure to the well-described SL thapsigargin and was found cytotoxic [3] due to acting by the same mechanism in cells [4]. It was, however, found that trilobolide may be modified in such a way that its cytotoxicity is reduced while the immuno-biological properties are retained [5].…”

“…We previously showed the preparation of fluorescent trilobolide conjugates [3] which retained the activity of parental compounds and proved to be useful for live-cell imaging. In this article, we present a similar approach for archangelolide.…”

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

“…1 ) is a potent natural compound of the sesquiterpene lactone class, which causes cell death via depleting intracellular Ca 2+ ion stores by the irreversible inhibition of sarco-/endoplasmic reticulum Ca 2+ -ATPase (SERCA) already at nanomolar concentrations [ 27 – 30 ]. In our recent study, we reported the localization of fluorescent Tb-BODIPY conjugates in the endoplasmic reticulum of a number of cancer cell lines [ 31 ]. Besides that, Tb is of high interest also for the fact that it induces high production of nitric monoxide (NO) which has an immunomodulating effect on rat peritoneal cells [ 32 ].…”

“…Besides that, Tb is of high interest also for the fact that it induces high production of nitric monoxide (NO) which has an immunomodulating effect on rat peritoneal cells [ 32 ]. We documented in [ 31 ] that Tb, prepared as a fluorescent conjugate with green-emitting BODIPY, induced a dose-dependent NO production in primary rat macrophages. The potency of the fluorescent Tb to express inducible NO and cytokine secretion was shifted to a low micromolar range in comparison to the submicromolar activity of Tb itself.…”