Biophysical studies of mutated K562 DNA (erythroleukemic cells) binding to adriamycin and daunomycin reveal that mutations induce structural changes influencing binding behavior

Abstract

K562 cells are erythroleukemic cells derived from a chronic myeloid leukemia patient in blast crisis. Comparison of the genome from K562 cells and normal human genome has been very useful strategy, in uncovering eight genes, implicated in acute myeloid leukemia (AML). These genes carry mutations in K562 genome and the role of these mutations in the progression and treatment of AML is still not known. Consequences of these mutations on drug DNA binding are also not known exactly. In the present study, mutation induced structural changes in K562 genome, compared to normal genome, are identified by Fourier transform infra red (FTIR) and circular dichroism (CD) spectroscopy. These structural changes in native K562 DNA favor stronger binding with binding constants 2.0 × 10⁸ and 1.9 × 10⁹ M⁻¹ with antileukemic drugs adriamycin and daunomycin (DNM), respectively, compared to normal DNA. On binding, these drugs disrupt the native B form structure of normal DNA to a greater extent, compared to A-like structure of K562 DNA. Fluorescence and absorption studies reveal higher intercalation as well as mixed groove binding of these drugs with K562 DNA compared to normal DNA. Among the drugs, DNM has higher affinity for K562 DNA.

Keywords:

• anthracyclines
• mutated DNA
• K562 cells
• FTIR
• CD
• normal genomic DNA

Acknowledgments

The authors are thankful to Dr. Abhijit Saha at UGC-DAE (University Grant Commission-Department of Atomic Energy) Center for Scientific Research for providing us the FTIR facility and his constant cooperation throughout the work. Thanks are also extended to Ms. Debosmita Ghosh at UGC-DAE Center for Scientific Research for her technical support and cooperation throughout the work without which this work would have not been possible. Dr Chabita Saha is thankful to Department of Science and Technology, Govt. of India for the financial support. Ms Debjani Ghosh, Junior Research Fellow is financially supported by National Tea Research Foundation (NTRF), India and is thankful to the same. Dr Maidul Hossain is a receipient of the Research Associateship of the Council of Scientific and Industrial Research (CSIR), Govt. of India.