A novel nickel(ii) complex of 6-methoxy-1-pyridine-β-carboline () was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 μM), lower than those of ligand and cisplatin. Furthermore, (6 μM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca] levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered executive molecular caspase-9 and caspase-3. In short, exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.
The real‐time tracking of localization and dynamics of small molecules in organelles helps to understand their function and identification of their potential targets at subcellular resolution. To identify the mitochondrion‐targeting effects of small molecules (NA‐17 and NA‐2a) in cancer cells, we used mass spectrometry to study their distribution and accumulation in mitochondria and in the surrounding cytoplasm thus enabling tracing of action processes of therapeutic compounds. Colocalization analysis with the aid of imaging agents suggests that both NA‐17 and NA‐2a display mitochondrion‐targeting effects. However, MS analysis reveals that only NA‐2a displays both a mitochondrion‐targeting effect and an accumulation effect, whereas NA‐17 only distributes in the surrounding cytoplasm. A combination of mitochondrion imaging, immunoblotting, and MS analysis in mitochondria indicated that NA‐17 neither has the ability to enter mitochondria directly nor displays any mitochondrion‐targeting effect. Further studies revealed that NA‐17 could not enter into mitochondria even when the mitochondrial permeability in cells changed after NA‐17 treatment, as was evident from reactive oxygen species (ROS) generation and cytochrome c release. In the process of cellular metabolism, NA‐17 itself is firmly restricted to the cytoplasm during the metabolic process, but its metabolites containing fluorophores could accumulate in mitochondria for cell imaging. Our studies have furnished new insights into the drug metabolism processes.
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