The Activity of Inducing Cancer Cell Death and Affecting Mitochondrial Function of a Novel Manganese-pyridine Compound

Abstract: In this study， anticancer activity of the novel manganese-pyridine compound Adpa-Mn(III) ([(Adpa)Mn(μ2-O)2Mn(Adpa)]PF6·8H2O (Adpa=bis(2-pyridylmethyl) amino-2-propionic acid)) and its possible mechanism were investigated. Four human cancer cell lines including HepG-2， HeLa， A549 and U251 cells were treated by manganese-pyridine derivative Adpa-Mn(III). Cancer cell proliferation were detected by MTT assay. To observe cell apoptosis， the morphological and nuclei changes in H2B-GFP-labled HeLa cells were observed by a live cell system (LCS). Autophagic cell death was studied with acidic vesicular organelles observation following monodansylcadervarine (MDC) labeling and autophagy-related proteins GFP-LC3 plasmid transfection. Mitochondrial membrane potential was observed by JC-1 staining; Intracellular free Ca2+ content was detected with Fluo-3 staining; Formation of ROS were detected by DCFH-DA staining. Our data show that Adpa-Mn(III) exhibited significant inhibition on cancer cell proliferation and exhibited dose- and time-dependent effect on U251 proliferation. Adpa-Mn(III) induced apoptosis indicated by chromatin condensation. Treartment of Adpa-Mn(III) enhanced fluorescence intensity of monodansylcadervarine (MDC) and GFP-LC3. Moreover， Adpa-Mn(III) induced mitochondrial membrane potential decreased， elevated ROS， and overloaded intracellular Ca2+. These results suggest that Adpa- Mn(III) exerts significant anticancer activity. Adpa-Mn(III) may induce apoptosis and autophagy of cancer cells. The possible mechanism underlying its anticancer effect was related to ROS-induced mitochondrial dysfunction. In summary， the current study suggest that Adpa-Mn(III) could be exploited as a potential lead compound as a novel anticancer metal-drug.

CSTR: 32200.14.cjcb.2012.06.0004