trans-Resveratrol (t-RES) is one of the most relevant and extensively investigated stilbenes with a broad spectrum of biological activities. In contrast to the detailed knowledge of t-RES activities in biological systems, much less is known about the effects of higher hydroxylated stilbenes. Therefore, the aim of this study was to evaluate the protective effects (antioxidant activities) of t-RES and two analogues: the natural metabolite piceatannol (PCA) and the synthesized 3,3',4,4',5,5'-hexahydroxy-trans-stilbene (HHS) against H 2 O 2-induced DNA damage in leukemic L1210, K562 and HL-60 cells using single-cell gel electrophoresis (SCGE). After 24 h pre-treatment of cells all compounds investigated significantly inhibited the incidence of DNA single strand breaks induced by H 2 O 2. The protective effects of PCA and HHS in L1210 cells and of HHS in HL-60 cells were significantly higher compared to the activity of t-RES (+ P<0.05). In K562 cells the differences of the antioxidant activities of PCA and HHS, and of PCA in HL-60 cells were of much higher significance when compared to t-RES (++ P<0.01). In conclusion, we can prove that all stilbenes investigated, t-RES, PCA, and HHS, manifested potent antioxidant effects on three leukemic cell lines and the presence of ortho-dihydroxy structures enhanced the protective effect against DNA damage caused by ˙OH radicals.

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Chemoresistance is a biological response of cells to survive toxic stress. During cancer treatment the development of chemoresistance is a major problem. The mechanisms how cells become insensitive, and which downstream pathways are affected are not completely understood. Since it has not been well analysed which and how many regulative disorders are subsummised under the term "chemoresistance", we examined and measured arabinosylcytosine (AraC)-mediated desensitation of two mechanisms relevant for tissue homeostasis, cell cycle inhibition and apoptosis induction. MCF-7 cells harbouring ectopic mutated p53 were suitable for this investigation because they activated these mechanisms subsequently and became insensitive to AraC with regard to cell cycle inhibition and apoptosis induction. The major causal mechanism of acquired resistance against AraC was most likely through the inhibition of the first step of AraC phosphorylation within the cell, which is rate limiting for its activation. With regard to cell cycle inhibition AraC-resistant cells were also resistant against 5-fluorodeoxyuridine (5-FdUrd), but fully responsive to 5-FdUrd-induced apoptosis, evidencing that cell cycle and apoptosis are independent of each other. Apoptosis correlated with AIF-activation and was independent of Caspase 7, whereas cell cycle inhibition correlated with cyclinD1 expression but not with induction of p21 or p27. The phosphate conjugated 5-FdUrd-araC heterodimer (5-Fluoro-2'-desoxyuridylyl-(3'-->5')-Arabinocytidine), which is a prodrug of AraC-monophosphate, reactivated AIF and down-regulated cyclin D1 in AraC-resistant cells and circumvented resistance to apoptosis and to cell cycle inhibition. Also, cells which were resistant to 5-FdUrd or doxorubicin were sensitive to 5-FdUrd-araC. This investigation demonstrates that chemoresistance affects apoptosis induction and cell cycle inhibition independently and that detailed knowledge about the affected downstream pathways would enable the design of targeted intervention with small molecules to restore chemosensitivity.

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