Survey of the binding affinities of anticancer drugs, mitoxantrone and actinomycin D, on rat liver chromatin

Actinomycin D and mitoxantrone are anticancer drugs widely used in the treatment of a variety of cancers. DNA has been introduced as a main target for these drugs which results in inhibition of both DNA replication and RNA transcription. In the cell nucleus، DNA is not naked but is complexed with histone proteins producing a compact structure called chromatin. In the present study we have investigated and compared the binding affinity of these drugs to rat liver chromatin. The results of gel electrophoresis and UV-Vis spectroscopy showed that both drugs bound to chromatin but mitoxantrone exhibited higher affinity compared to actinomycin D. Disappearance of histones on the gel and reduction of the absorbencies at 608 and 440 nm، corresponding mitoxantrone and actinomycin D respectively، suggest compaction/aggregation of the chromatin. The binding isotherms demonstrated a positive cooperative binding pattern for both drugs with binding constants (ka) of 7. 1×106 M-1 and 0. 35×105 M-1 for mitoxantrone and actinomycin D respectively suggesting higher binding affinity of mitoxantrone to chromatin compared to actinomycin D. In addition Gibbs free energy for the binding of both drugs was negative demonstrating that the reaction is spontaneously. It is concluded that actinomycin D preferentially interacts with DNA molecule، whereas، mitoxantrone binds to nucleoprotein structure of chromatin implying the role of histone proteins in this binding process.