Inhibition of the cytotoxicity of protein toxins by a novel plant metabolite, Mansonone-D

Abstract

We have studied the effect of several structurally related mansonones on the cytotoxicity of plant and bacterial toxins in Vero and BER-40, a brefeldin A-resistant mutant of Vero cells. Mansonone-D (MD), a sesquiterpenoid ortho-naphthoquinone, inhibited the cytotoxicity of ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in Vero cells to different extents. The inhibition of ricin cytotoxicity was dose dependent and reversed upon removal of the drug. Protection of ricin cytotoxicity was also observed in the presence of cycloheximide, indicating that de novo protein synthesis is not required for the protective effect. Although MD inhibited the degradation and excretion of ricin, the binding and internalization of ricin was not affected. In contrast, MD strongly reduced the specific binding of diphtheria toxin in Vero cells. Fluorescence microscopic studies show that MD treatment dramatically alters the morphology of the Golgi apparatus in Vero cells. The kinetic studies reveal that the protection of ricin cytotoxicity is the consequence of decreased toxin translocation to the cytosol in MD-treated cells. The reactive ortho-quinone moiety of MD is important for the protective effect as thespesone, a para-naphthoquinone with a heterocyclic ring structure identical to that of MD, did not inhibit the cytotoxicity of toxins. Thespone, a dehydromansonone-D, lacking two hydrogens from the heterocyclic dihydrofuran ring of MD, inhibited the cytotoxicity of ricin, but was albeit less potent than MD. Neither mansonone-E nor mansonone-H with reactive ortho-quinone moiety, but with a different heterocyclic structure, had any effect on the cytotoxicity of ricin indicating that the protective effect of MD is specifically related to the overall structure of the metabolite.

Total Synthesis and Anticancer Activities of (−)- and (+)-Thespesone

“…They were isolated from extracts of the reddish brown heartwood. 7 Some of them have cytotoxic, antifungal, or antioxidant properties. [5][6][7][8] (-)-Thespesone 1 was first isolated in 1983 9 but was not fully characterized until 2004.…”

“…It was also reported to have antifungal, antibiotic, antifertility, antibacterial, anti-inflammatory, antioxidant, purgative, hepatoprotective, and antitumor properties. − The constituents believed responsible for the majority of these effects are so-called mansonones, highly oxo-functionalized sesquiterpenes of the cadinane type. They were isolated from extracts of the reddish brown heartwood . Some of them have cytotoxic, antifungal, or antioxidant properties. − (−)-Thespesone 1 was first isolated in 1983 but was not fully characterized until 2004 .…”

“…They were isolated from extracts of the reddish brown heartwood . Some of them have cytotoxic, antifungal, or antioxidant properties. − (−)-Thespesone 1 was first isolated in 1983 but was not fully characterized until 2004 . Herein we describe its total synthesis and the cytotoxicities of the two enantiomers and the racemate of thespesone against a panel of six cancer cell lines and nonmalignant foreskin fibroblasts.…”