Anti-tumor activities of Salograviolide A, derivatives, and nanoparticle formulations in breast and colorectal cancer cells -

Abstract

We are currently witnessing a renewed interest in the use of natural compounds to treat cancer. Sesquiterpene lactones are plant secondary metabolites that possess a broad range of anti-tumor activities due to the reactivity of their alkylating centers, lipophilicity, and molecular geometry. We have isolated the sesquiterpene lactone, Salograviolide A (Sal A), from the indigenous Lebanese plant Centaurea ainetensis, and have previously shown that this compound exhibits promising anti-cancer properties in a variety of cancer cells, while sparing normal ones. Combining nanotechnology with medicine enables more efficient drug delivery; increasing stability, bioavailability, and reducing drug toxicity, which are common challenges in drug development. The general aim of this study is to develop more bioavailable and clinically desirable derivatives of Sal A. We aimed to formulate and characterize nanoparticles of Sal A and its derivatives and assess the anti-cancer effects in established in vitro models of colorectal and breast cancer.We have successfully scaled up the extraction and purification of Sal A using preparative high performance liquid chromatography during which another compound with similar physiochemical properties eluted at a later time point which was identified as Salograviolide B (Sal B). Importantly, this will be the first report revealing the biological activities of this sesquiterpene lactone. Furthermore, we have successfully synthesized derivatives of Sal A and Sal B: Sal A-1, Sal A-2, and Sal B-1 and have assayed their cytotoxicity on normal cells. These five compounds exhibited anti-cancer activities in a variety of human cancer cell lines where the different derivatives have shown at least a two-fold increased potency relative to Sal A. This increased potency may be attributed to their increased hydrophobicity, as confirmed through solubility experiments. By determining the aqueous and organic solubility of the compounds, we were able to ascertain their suitability for producing na