Growth-Inhibiting Activity of Resveratrol Imine Analogs on Tumor Cells In Vitro

Abstract

Although resveratrol exerts manifold antitumorigenic effects in vitro, its efficacy against malignancies in vivo seems limited. This has been increasingly recognized in recent years and has prompted scientists to search for structurally related compounds with more promising anticarcinogenic and/or pharmacokinetic properties. A class of structurally modified resveratrol derivatives, so-called resveratrol imine analogs (IRA’s), might meet these requirements. Therefore, the biological activity of five of these compounds was examined and compared to that of resveratrol. Firstly, the antiproliferative potency of all five IRA’s was investigated using the p53 wildtype-carrying colorectal carcinoma cell line HCT-116wt. Then, using the former and a panel of various other tumor cell lines (including the p53 knockout variant HCT-116p53-/-), the growth-inhibiting and cell cycle-disturbing effects of the most potent IRA (IRA 5, 2-[[(2-hydroxyphenyl)methylene]amino]-phenol) were studied as was its influence on cyclooxygenase-2 expression and activity. Finally, rat liver microsomes were used to determine the metabolic stability of that compound. IRA 5 was clearly the most potent compound in HCT-116wt cells, with an unusually high IC50-value of 0.6 μM. However, in the other five cell lines used, the antiproliferative activity was mostly similar to resveratrol and the effects on the cell cycle were heterogeneous. Although all cell lines were affected by treatment with IRA 5, cells expressing functional p53 seemed to react more sensitively, suggesting that this protein plays a modulating role in the induction of IRA 5-mediated biological effects. Lastly, IRA 5 led to contradictory effects on cyclooxygenase-2 expression and activity and was less glucuronidated than resveratrol. As IRA 5 is approximately 50 times more toxic towards HCT-116wt cells, exerts different effects on the cyclooxygenase-2 and is metabolized to a lesser extent, it shows certain advantages over resveratrol and could therefore serve as basis for additional chemical modifications, potentially yielding compounds with more favorable biological and pharmacokinetic features.

Effects of a Grapevine Shoot Extract Containing Resveratrol and Resveratrol Oligomers on Intestinal Adenoma Development in Mice: In Vitro and In Vivo Studies

“…Cytotoxicity (i.e., changes in cell number/mass) was assessed by means of the sulforhodamine B (SRB) assay, which was performed as previously described, with slight variations . Briefly, 1000 APC10.1 cells were seeded in 96‐well plates and treated once with the solvent (0.1% DMSO) or the test compounds for 48, 72, and 120 h. In order to mimic the animal's daily Vineatrol®30 consumption during the in vivo experiment, the APC10.1 cells were also treated with the above‐mentioned compounds on a daily basis for 48, 72, and 120 h. Finally, the absorption was recorded at 492 nm using a plate reader (Infinite® 200; Tecan, Crailsheim, Germany).…”

“…The cell cycle analysis was mostly performed as described beforehand . Cells (0.5 × 10 6 ) were seeded on 10 cm dishes and treated with the different test substances for 24, 48, and 72 h. After each incubation time point, APC10.1 cells were collected, fixed in ethanol (70%) and stored at 4 °C until analysis.…”

Gnetin‐C and other resveratrol oligomers with cancer chemopreventive potential

“…The synthetic tert ‐butylated analogs of resveratrol and the oligomers pallidol and quadrangularin A synthetized via biomimetic oxidative dimerization were recently reported to be more potent than their native counterparts at inhibiting the growth of TF1 leukemia cells . The antitumor activity of the synthetic resveratrol analogue IRA 5 in HCT‐116 cells was 50‐fold stronger than that of resveratrol . In addition, chemical modifications of the backbone structure of resveratrol have been shown to improve its pharmacokinetic parameters.…”

Phytotherapeutics in cancer invasion and metastasis

“…Several biological properties have been ascribed to resveratrol, including anticancer activity in animal models (Chimento et al, ; Kim, Hwang, & Choi, ; Sinha, Sarkar, Biswas, & Bishayee, ; Varoni, Faro, Sharifi‐Rad, & Iriti, ; Wang et al, ). However, the evidence about its efficacy in humans remains controversial (Vang et al, ), probably due to its low bioavailability (Walle, Hsieh, DeLegge, Oatis, & Walle, ).…”