Live cell cytotoxicity studies: documentation of the interactions of antitumor active dirhodium compounds with nuclear DNA.
The promising antitumor activity of dirhodium complexes has been known for over 30 years. There remains, however, a general lack of understanding of their activity in cellulo. In this study, we report the DNA interactions and activity in living cells of six monosubstituted dirhodium(II,II) complexes of general formula [Rh(2)(mu-O(2)CCH(3))(2)(eta(1)-O(2)CCH(3))(L)(CH(3)OH)](+), where L = bpy (2,2'-bipyridine) (1), phen (1,10-phenanthroline) (2), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline) (3), dppz (dipyrido[3,2-a:2',3'-c]phenazine) (4), dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) (5), and dap (4,7-dihydrodibenzo[de,gh][1,10]phenanthroline) (6). DNA interactions were investigated by UV/visible spectroscopy, relative viscosity measurements, and electrophoretic mobility shift assay. These measurements indicate that compound 5 exhibits the strongest interaction with DNA. Compound 5 also causes the most damage to DNA after cellular internalization, as evaluated by the alkaline comet assay. Compound 5, however, is not the most effective at inhibiting cell viability of the human cancer cells HeLa and COLO-316. The greater hydrophobicity of 5 as compared to that of 4, which is the most effective compound in the series, hinders its ability to reach its cellular target(s). Data from modulation studies of glutathione using N-acetylcysteine and L-buthionine-sulfoximine indicate that changes in glutathione levels do not affect the activity of these particular dirhodium complexes. These results suggest that glutathione is not the only agent involved in the deactivation of these dirhodium complexes.
Aguirre
J Dafhne
JD
Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA.
Angeles-Boza
Alfredo M
AM
Chouai
Abdellatif
A
Pellois
Jean-Philippe
JP
Turro
Claudia
C
Dunbar
Kim R
KR
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D020552:Comet Assay; D004247:DNA / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D012238:Rhodium / Q000737:chemistry / Q000494:pharmacology*; D014783:Viscosity / Q000187:drug effects
D000970:Antineoplastic Agents; D004247:DNA; C427203:calf thymus DNA; D012238:Rhodium; D005978:Glutathione