Cytotoxicity, apoptosis, and in vitro DNA damage induced by potassium chromate.
Cr(6+) is a known human cytotoxic and carcinogenic agent that requires intracellular reduction for activation. We have analyzed the cytotoxic and DNA binding properties of K(2)CrO(4) (Cr(6+)) in comparison with those of Cl(3)Cr (Cr(3+)). The results indicate that K(2)CrO(4) exhibits higher cytotoxicity than Cl(3)Cr in several human and murine cell lines. The cytotoxic activity of K(2)CrO(4) is also indicated by the fact that is able to produce cell killing through apoptosis in cisplatin-resistant cells transformed by H-ras oncogene. Moreover, in vitro DNA binding experiments show that, in the presence of ascorbate (the major intracellular reductant of Cr(6+)), K(2)CrO(4) induces both interstrand cross-links and strand breaks. Because the chromate anion is by itself unreactive toward DNA, these data suggest that the cytotoxicity of K(2)CrO(4) may be associated with the DNA binding of reactive intermediate chromium species resulting from reduction of Cr(6+).
Flores
A
A
Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Madrid, 28049, Spain.
Pérez
J M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001205:Ascorbic Acid / Q000378:metabolism; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism / Q000633:toxicity; D002840:Chromates / Q000378:metabolism / Q000633:toxicity*; D017608:Chromium Compounds / Q000378:metabolism / Q000633:toxicity; D002942:Circular Dichroism; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010957:Plasmids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017680:Potassium Compounds / Q000378:metabolism / Q000633:toxicity*; D019163:Reducing Agents / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D002712:Chlorides; D002840:Chromates; D017608:Chromium Compounds; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D011089:Polydeoxyribonucleotides; D017680:Potassium Compounds; D019163:Reducing Agents; C019530:poly(dC-dG); C027373:potassium chromate(VI); D018631:ras Proteins; C022990:chromic chloride; D001205:Ascorbic Acid; D002945:Cisplatin