Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK1). Viability of LLC-PK1 cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100-400 microM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10-25 microM and reaching a plateau between 50 and 100 microM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100-500 microM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 microM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role.

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[Effect of local DNA conformation on bis-netropsin binding in the minor DNA groove].

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[Effect of DNA local conformation on the affinity and binding specificity of bis-netropsins to DNA].

The interaction of short nucleotide duplexes with bis-netropsins, in which netropsin fragments are linked in the tail-to-tail orientation via cis-diammineplatinum group (<--Nt-Pt(NH3)-Nt-->) or aliphatic pentamethylene chain (<--Nt-(CH2)5-Nt-->), has been studied. Both the bis-netropsins have been shown to bind to DNA oligomer 5'-CCTATATCC-3' (I) as a hairpin with parallel orientation of netropsin fragments in 1:1 stoichiometry. Monodentate binding has been detected upon binding of bis-netropsins to other duplexes of sequences 5'-CCXCC-3'--where X = TTATT (II), TTAAT (III), TTTTT (IV), and AATTT (V)--along with the binding of bis-netropsins as a hairpin. The formation of dimeric antiparallel motif between the halves of two bound bis-netropsin molecules has been observed in the complexes of <--Nt-(CH2)5-Nt--> with DNA oligomers IV and V. The ratio of binding constant of bis-netropsin as a hairpin (K2) to monodentate binding constant (K1) has been shown to correlate with the width and/or conformational lability of DNA in the binding site. The share of bis-netropsin bound as a hairpin decreases in the order: TATAT > TTATT > TTAAT > TTTTT > AATTT, whereas the contribution of monodentate binding rises. The minimal strong binding site for <--Nt-Pt(NH3)-Nt--> and <--Nt-(CH2)5-Nt--> binding as a hairpin has been found to be DNA duplex 5'-CGTATACG-3'.

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