Myricetin arrests Human Telomeric G-quadruplex structure: A new mechanistic approach as an anticancer agent
Soma Mondal, Jagannath Jana, Pallabi Sengupta, Samarjit Jana, Subhrangsu Chatterjee
Small molecules arresting G-quadruplex structure has become a potential strategy for the development and designing of new class of anticancer therapeutics. We have studied the interaction of Myricetin, a plant flavonoid and a putative anticancer agent with human telomeric G-quadruplex TTAGGG(TTAGGG)3 DNA. Reverse Transcription PCR data revealed significant repression in hTERT expression in MCF-7 breast cancer cells upon increasing concentration of Myricetin. Further, we conducted telomeric repeat amplification protocol assay to confirm the inhibition of telomerase by Myricetin. Optical spectroscopic techniques like Circular Dichroism, UV spectrocopy and Fluorescence Spectroscopy revealed the formation of stable Myricetin-G-quadruplex complex. The thermodynamic parameters of Myricetin-G-quadruplex complex formation presented through Isothermal Titration Calorimetry studies, indicate the binding process to be thermodynamically favorable. In addition, high resolution NMR spectroscopy in conjunction with Molecular Dynamics Simulation is employed to provide detail mechanistic insights of binding of Myricetin-G-quadruplex complex at atomic level. Our results thus propose a new mode of action of Myricetin as an anticancer agent via arresting telomeric G-quadruplex structure.
Circular dichroism, Secondary structure, DNA structure, Ligand binding, Thermal stability, Thermodynamics, Biochemistry