Antiproliferative Effects in Colorectal Cancer and Stabilisation in Cyclodextrins of the Phytoalexin Isorhapontigenin

Abstract

Isorhapontigenin has been proposed as a better alternative for oral administration than the famous resveratrol, as it shares many biological activities, but with a structure that could make its delivery easier. Although this hydrophobic structure could enhance bioavailability, it could also be a disadvantage in the development of products. In this research, we study the antiproliferative activity of this stilbene against colorectal cancer and overcome its limitations through molecular encapsulation in cyclodextrins. The cytotoxic activity against human colorectal cancer cells of isorhapontigenin was similar to that of resveratrol or piceatannol, supporting its use as a bioactive alternative. The study of the encapsulation through fluorescence spectroscopy and molecular docking revealed that the complexation satisfies a 1:1 stoichiometry and that HP-β-CD is the most suitable CD to encapsulate this stilbene. Through a spectrophotometric assay, it was observed that this CD could double the basal water solubility, exceeding the solubility of other hydroxylated stilbenes. The stability of these inclusion complexes was higher at a pH below 9 and refrigeration temperatures. Moreover, the use of CDs retained more than 78% of isorhapontigenin after storage for 12 weeks, compared to 15% in free form. Overall, these findings could help design novel formulations to better deliver isorhapontigenin.

Keywords: cancer; encapsulation; isorhapontigenin; solubility; stability; stilbene.

Figure 1

Cytotoxicity of isorhapontigenin, resveratrol and piceatannol on human colorectal cancer cell line (Caco-2) after 48 h treatment. * Significance p < 0.05.

Figure 2

(A) Relative fluorescence of isorhapontigenin after encapsulation in HP-β-CD (25 °C pH 7). (B) Benesi–Hildebrand fitting of HP-β-CD complexation for (●) 1:1 model and (▽) 1:2 model.

Figure 3

Variation in the encapsulation constants of isorhapontigenin complexes with HP-β-CD, with (A) pH and (B) temperature.

Figure 4

Molecular docking of isorhapontigenin with (A) α-CD, (B) β-CD, (C) γ-CD, (D) HP-β-CD and (E) M-β-CD. The flexible CD atoms are coloured orange and non-flexible atoms blue. Hydrogen bonds are yellow dotted lines.

Figure 5

Improvement in the properties of isorhapontigenin after complexation with cyclodextrin. (A) Aqueous solubility at 25 °C, (B) stability at 25 °C pH 7, (C) stability spectrum of isorhapontigenin without cyclodextrins, (D) stability spectrum of isorhapontigenin with 5 mM of HP-β-CD. * Significance p < 0.05.