Molecular recognition of 3+1 hybrid human telomeric G-quadruplex DNA d-[AGGG(TTAGGG)(3)] by anticancer drugs epirubicin and adriamycin leads to thermal stabilization

摘要

Recent reports suggest influence of anti-cancer anthracyclines on telomere dysfunction and their possible interaction with G-quadruplex (G4) DNA as an alternate pathway to apoptosis. We have investigated interaction of epirubicin and adriamycin with G4 DNA [d-AGGG(TTAGGG)(3)] comprising human telomeric DNA sequence by surface plasmon resonance, absorption, fluorescence, circular dichroism and thermal denaturation. Epirubicin and adriamycin bind with affinity, K-b, = 2.5 x 10(5) and 5.2 x 10(5) M-1, respectively in monomeric form leading to decrease in absorbance, fluorescence quenching and ellipticity changes without any significant shift in absorption emission maxima with corresponding induced thermal stabilization by 13.0 and 11.6 degrees C in K+ rich solution. Na+ ions did not induce any thermal stabilization. Molecular docking confirmed external binding at grooves and loops of G4DNA involving 4OCH(3) of ring D, 9COCH(2)OH of ring A, 4'OH/H and 3'NH3+ of daunosamine sugar. Thermal stabilization induced by specific interactions is likely to hamper telomere association with telomerase enzyme and contribute to drug-induced apoptosis in cancer cell lines besides causing damage to duplex DNA. The findings pave the way for drug designing in view of immense possibilities of altering substituent groups on anthracyclines for enhancement of efficacy, reduced cell toxicity as well as specificity towards G-quadruplex DNA. (c) 2019 Elsevier B.V. All rights reserved.