title: Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: inhibition of ribonucleotide reductase activity.
abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene; RV), an ingredient of wine, exhibits a broad spectrum of antiproliferative effects against human cancer cells. In order to enhance these effects, we modified the molecule by introducing additional methoxyl and hydroxyl groups. The resulting novel RV analogs, M5 (3,4',5-trimethoxy-trans-stilbene), M5A (3,3',4,5'-tetramethoxy-trans-stilbene) and M8 (3,3',4,4',5,5'-hexahydroxy-trans-stilbene) were investigated in HT29 human colon cancer cells. Cytotoxicity was evaluated by clonogenic assays and the induction of apoptosis was determined using a specific Hoechst/propidium iodide double staining method. Cell cycle distribution was evaluated by FACS. The influence of M8 on the concentration of deoxyribonucleoside triphosphates (dNTPs), the products of ribonucleotide reductase (RR), was determined by high-performance liquid chromatography. M5 and M5A caused a dose-dependent induction of apoptosis and led to remarkable changes of the cell cycle distribution. After treatment with M5, growth arrest occurred mainly in the G2-M phase, whereas incubation with M5A resulted in arrest in the G0-G1 phase of the cell cycle. Incubation of HT29 cells with M8 produced a significant imbalance of intracellular dNTP pools, being synonymous with the inhibition of RR activity. The dATP pools were abolished, whereas the dCTP and dTTP pools increased. Due to these promising results, the investigated RV analogs deserve further preclinical and in vivo testing.
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.forename: Michael
authors.initials: M
authors.lastname: Pemberger
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Horvath
authors.forename: Ivo
authors.initials: I
authors.lastname: Savinc
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Norbert
authors.initials: N
authors.lastname: Handler
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Walter
authors.initials: W
authors.lastname: Jaeger
authors.forename: Monika
authors.initials: M
authors.lastname: Fritzer-Szekeres
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
mesh_terms: D000840:Anisoles / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003854:Deoxyribonucleotides / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013267:Stilbenes / Q000138:chemical synthesis / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: C514772:3,3',4,4',5,5'-hexahydroxystilbene; C530497:3,3',4,5'-tetramethoxystilbene; C497286:3,4',5-trimethoxystilbene; D000840:Anisoles; D000970:Antineoplastic Agents; D003854:Deoxyribonucleotides; D013267:Stilbenes; D011748:Pyrogallol; D012264:Ribonucleotide Reductases; D000077185:Resveratrol