CHELATION OF DIVALENT CATIONS AND ANTI-CANCER ACTIVITYOF 8-HYDROXYSTYRYLQUINOLINE DERIVATIVES IN VITRO

Abstract

Background. The search for new methods of cancer treatment and diagnosis are important. The disadvantages of chemotherapy drugs are the rapid acquisition of resistance and high toxicity. 8-hydroxyquinoline derivatives have a wide spectrum of biological activity and have the necessary properties for fluorescent cancer diagnosis. The aim of the study was to determine the chelation of calcium, magnesium and zinc cations by hydrophobic derivatives of 8-hydroxystyrylquinolines (8HQ) 2-(4-chlorostyryl)quinolin-8-ol (STQ-Cl) and 2-(4-nitrostyryl)quinolin-8-ol (STQ-NO2) in physiological solution, the stability of the complexes and the cytotoxicity of the compounds to prostate and breast cancer cell lines in vitro. Methods. 8HQ derivatives STQ-Cl and STQ-NO2 were used. Solutions of Ca2+, Mg2+, Zn2+ cations were prepared by the method of two-fold dilutions in 0.5-0.0078125 mM concentration range based on 0.9 % NaCl. Both individual solutions of each cation and a mixture in an equivalent molar ratio were used. The concentration of 8HQ derivatives were 0.05 mM. Optical absorption was registered in 200-700 nm wavelength range. Cytotoxicity was investigated on breast (MDA-MB-231) and prostate (DU-145) cancer cell lines. STQ-Cl and STQ-NO2 derivatives in DMSO were added to the incubation solution by four-fold dilutions (0.125–0.00003 mM). For luminescence studies, MDA-MB-231 and DU-145 cells were grown on coverslips. The final concentration of 8HQ derivatives were 5 mM. Cells were kept for 5, 10, 20 and 30 min. Luminescence was recorded under the same conditions for all samples, with an exposure time of 10 ms. Results. Mg2+ and Ca2+ (0.03125 mM) were contributed to reduce the intensity of optical absorption maxima of STQ-Cl by 1.6 and 1.3 times, respectively. The effect was most pronounced at 0.015625 mM Zn2+. Weak differences in the optical absorption of solutions were detected when STQ-NO2 was incubated with different concentrations of Mg2+ and Ca2+. The optical absorption intensity of the STQ-NO2 aqueous solution was increased at 0.015625 and 0.03125 mM Zn2+. The maximum cytotoxicity against MDA-MB-231 cells for STQ-Cl was about 80 %, and STQ-NO2 was 60 % at 0.04 mM Zn2+. DU-145 cells were more sensitive to STQ-NO2 (EC50 = 0.011 mM), but weakly sensitive to STQ-Cl (50 % at 0.125 mM). The maximum luminescence intensity was after 20 min of incubation with STQ-Cl and STQ-NO2 (5 mM) for both cells lines and was not change over time. Conclusions. The decrease of optical absorption maxima of STQ-Cl aqueous solutions in the presence of magnesium, calcium, and zinc cations was a consequence of aggregation processes. This phenomenon was probably the reason for the different cytotoxicity of STQ-Cl and STQ-NO2, as well as the presence of other mechanisms of action to cancer cells. Results was a consequence of different affinity of 8-hydroxyquinoline derivatives to magnesium, calcium and zinc cations, solubility in water, stability, aggregation of metal complexes and free compounds.