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

Hajihassan, Zahra; Rabbani-Chadegani, Azra

doi:10.22051/jab.2015.1966

Document Type : Research Paper

Authors

https://doi.org/10.22051/jab.2015.1966

Abstract

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 (k_a) of 7.1×10⁶M^-1 and 0.35×10⁵M^-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.

Keywords

References

Agarwal S., Jangir D.K., Mehrotra R. (2013) Spectroscopic studies of the effect of anticancer drug mitoxantrone interaction with calf thymus DNA. J. Photochem. Photobiol. B. 120: 177-182.

Aivasashvilli V.A. and Beabealashvilli, R.S. (1983) Sequence-specific inhibition of RNA elongation by actinomycin D. FEBS Lett., 160: 124–128.

Bradbury E.M., Van Hold K. (2004) Chromatin structure and dynamics: a historical perspective. New Compr Biochem. 39:1-11

Burgoyne L.A., Wagar M.A., Atkinson M.R. (1970) Calcium-dependent priming of DNA synthesis in isolated rat liver nuclei. Biochem. Biophys. Res. Commun., 39: 254-259.

Cacchione S., Caneva R., Savino M. (1986) Selective binding of actinomycin D induces a reversible conformational transition of nucleosomes. Biochim. Biophys. Acta, 867(4): 229-33.

Cesconetto E.C., Junior F.C., Crisafuli F.A., Mesquita O.N., Ramos E.B., Rocha, M.S. (2013) Dna interaction with actinomycin D: mechanical measurements reveal the details of the binding data. Phy. Chem. Che. Pys. 15: 11070-11077.

Chan A., Lo-Coco F. (2013) Mitoxantrone-related acute leukemia in MS: an open or closed book. Neurology 80: 1529-1533.

Enache M., Volanschi E. (2008) Fluorescence study of the interaction of antitumor drug actinomycin D with double stranded DNA. Revue. Roumaine de Chimie., 53(9): 841–846.

Faulds D., Balfour J.A., Chrisp P., Langtry H.D. (1991) Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the chemotherapy of cancer. Drugs., 41(3): 400-49.

Freifelder D.M. (1982) Physical Biochemistry. 2^nd edition., chapter 15,.W.H. Freeman,Inc. pp 537-572., NewYork.

Hajihassan Z., Rabbani-Chadegani A. (2009) Studies on the binding affinity of anticancer drug mitoxantrone to chromatin, DNA and histone proteins. J. Biomed. Sci. 16(1): 31.

Hajihassan Z., Rabbani-Chadegani A. (2011) Interaction of mitoxantrone as an anticancer drug with chromatin proteins, Core hitone and H1 in solution. Int. J. Biol. Macromol. 48: 87-92.

Koba M., Konopa J. (2005) Actinomycin D and its mechanisms of action. Postepy Hig. Med. Dosw. 59: 290-298.

Laemmli U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature., 227: 680-685.

Lewis J.L. (1972) Chemotherapy of gestational choriocarcinoma, Cancer. 30: 1517–1521.

Li N., Ma Y., Yang C., Guo L., Yang X. (2005) Interaction of anticancer drug mitoxantrone with DNA analyzed by electrochemical and spectroscopic methods. Biophys. Chem. 116: 199-205.

Liu X., Chen H., Patel D.J. (1991) Solution structure of actinomycin-DNA complexes: drug intercalation at isolated G-C sites. J. Biomol. NMR. 1(4): 323-47.

Lown J.W., Morgen A.R., Yen S.F., Wang Y.H. and Wilson D.W. (1985) Characteristics of the binding of the anticancer agent's mitoxantrone and ametantrone and related structures to deoxyribonucleic acids. Biochemistry., 24: 4028-4035.

Nishio A., Uveki E.M. (1983) Cellular uptake and inhibition of DNA synthesis by dihydroxy anthraquinone and two analogues. Cancer.Res., 43(5): 1951-1956.

Ory S., Debouverie M., Le Page E., Pelletier J., Malikova I., Gout O., Edan G. (2008) Use of mitoxantrone in early Multiple Sclerosis with malignant disease course. Observational study in 30 patients with clinical and MRI outcomes after one year. Rev.Neurol (Paris)., 164(12): 1028-1034.

Rabbani A., Iskander M., Ausio J. (1999) Daunomycin-induced unfolding and aggregation of chromatin. J. Biol. Chem., 274: 18401-18406.

Rabbani-Chadegani A., Keyvani-Ghamsari S. and Zarkar N. (2011) Spectroscopic studies of dactinomycin and vinorelbine binding to deoxyribonucleic acid and chromatin. Spectrochimica. Acta .Part A: Molecular and Biomolecular Spectroscopy., 84(1): 62-67.

Rapkin L.M., Anchel D.R., Li R., Bazell-Jones D.P. (2012) A view of the chromatin landscape. Micron 43: 150-158.

Rosenberg L.S., Carvlin M.J., Krugh T.R. (1986) The antitumor agent mitoxantrone binds cooperatively to DNA: Evidence for heterogeneity in DNA conformation. Biochemistry., 25: 1002-1008.

Scatchard G. (1949) The attraction of proteins for small molecules and ions. Ann.N.Y.Acad.Sci., 51: 660-672.

Scott L.J., Figgitt D.P. (2004) Mitoxantrone: a review of its use in multiple sclerosis. CNS Drugs 18: 379-396.

Sha F., Chen F.M. (2000) Actinomycin D Binds Strongly to d (CGACGACG) and d(CGTCGTCG). Biophys. J. 79(4): 2095-2104.

Snyder J.G., Hartman N.G., D'Estantoit B.L., Kennard O., Remeta D.P., Breslauer K.J. (1989) Binding of actinomycin D to DNA: evidence for a nonclassical high-affinity binding mode that does not require GpC sites. Proc. Natl. Acad .Sci. U S A., 86(11): 3968-72.

Applied Biology

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

References

References

Volume 28, Issue 1 - Serial Number 1
October 2015
Pages 23-36

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

References

References

Volume 28, Issue 1 - Serial Number 1October 2015Pages 23-36

Volume 28, Issue 1 - Serial Number 1
October 2015
Pages 23-36