Abstract
The drug, di-2-pyridylketone-2-pyridine carboxylic acid hydrazone (DPPCAH) and its copper complex (DPPCAH-Cu) exhibit significant antitumor activity. However, the mechanism of their pharmacological interaction with the biological molecule bovine serum albumin (BSA) remains poorly understood. The present study elucidates the interactions between the drug and BSA through MTT assays, spectroscopic methods and molecular docking analysis. Our results indicate that BSA could attenuate effect on the cytotoxicity of DPPCAH, but not DPPCAH-Cu. Data from fluorescence quenching measurements demonstrated that both DPPCAH and DPPCAH-Cu could bind to BSA, with a reversed effect on the environment of tryptophan residues in polarity. CD spectra revealed that the DPPCAH-Cu exerted a slightly stronger effect on the secondary structure of BSA than DPPCAH. The association constant of DPPCAH with BSA was greater than that of DPPCAH-Cu. Docking studies indicated that the binding of DPPCAH to BSA involved a greater number of hydrogen bonds compared to DPPCAH-Cu. The calculated distances between bound ligands and tryptophans in BSA were in agreement with fluorescence resonance energy transfer results. Thus, the binding affinity of the drug (DPPCAH or DPPCAH-Cu) with BSA partially contributes to its antitumor activity; the greater the drug affinity is to BSA, the less is its antitumor activity.
Highlights
Neoplastic cells need higher concentrations of iron and copper for their growth than normal cells [1,2], so the development of novel Fe and Cu chelators has become a promising anticancer strategy owing to their ability to inhibit cancer cell proliferation [3]
As shown in bovine serum albumin (BSA) attenuated the growth inhibition of HepG2 cells mediated by di-2-pyridylketone-2-pyridine carboxylic acid hydrazone (DPPCAH), but not DPPCAH-Cu, the growth inhibition of HepG2 cells mediated by DPPCAH, but not DPPCAH-Cu, indicating that indicating that the effect of BSA on uptake or cytotoxicity of the drug was drug dependent, which was the effect of BSA on uptake or cytotoxicity of the drug was drug dependent, which was consistent consistent with earlier reports with earlier reports
Kq values calculated for DPPCAH and DPPCAH-Cu ranged from suggesting12that DPPCAH and10DPPCAH-Cu quenched the intrinsic fluorescence of BSA mainly by
Summary
Neoplastic cells need higher concentrations of iron and copper for their growth than normal cells [1,2], so the development of novel Fe and Cu chelators has become a promising anticancer strategy owing to their ability to inhibit cancer cell proliferation [3]. Information related to the effect of the interactions of metal chelating agents with biological molecules, such as human serum albumin (HSA) or bovine serum albumin (BSA) and DNA and their contribution to cytotoxicity has received limited attention. Mainly information the effect of the interactions of metal chelating agents with biological such asalbumin human serum albumin (HSA) or bovine serum albumin (BSA). The interaction of BSA with endogenous are available for investigating protein-ligand binding, such as equilibrium dialysis, fluorescence, and exogenous ligands mostly occurs in these domains. BSA, which calorimetry, and nuclear magnetic resonance [18], yet spectral techniques are widely used in could provide additional insight into the differences in antitumor activity detected between these determining the ligand and biomacromolecule interactions, our choice. BSA attenuated the growth inhibition of HepG2 cells mediated by DPPCAH, but not DPPCAH-Cu, the growth inhibition of HepG2 cells mediated by DPPCAH, but not DPPCAH-Cu, indicating that indicating that the effect of BSA on uptake or cytotoxicity of the drug was drug dependent, which was the effect of BSA on uptake or cytotoxicity of the drug was drug dependent, which was consistent consistent with earlier reports with earlier reports [13]. [13]
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