Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Abstract

Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic a-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several a-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined. Two highly metastatic cancer cell lines were incubated with three Cat S-specific compounds (6n, 6w and 6r) to analyze their effect on cellular Cat S activity and cell migration. At a 100 nM concentration, compounds 6n, 6r and 6w effectively inhibited Cat S activity. Cat S activity and cell migration were significantly reduced in CL1-3 cells after treatment with either 6n or 6w at 5 mM. Similar results were also obtained when A2058 cells were treated with 6n. These results highlight the therapeutic potential of a-ketoamide compounds, especially 6n and 6w, to prevent or delay cancer metastasis.

Synthesis and preliminary radiopharmacological characterisation of an 11C‐labelled azadipeptide nitrile as potential PET tracer for imaging of cysteine cathepsins

“…Based on the successfully established radiosynthesis of [ 11 C] 2 , its radiopharmacological investigation in nude mice bearing tumour xenografts derived from MDA‐MB‐231 STn‐Luc cells using PET imaging was enabled. The expression of the oncologically relevant cysteine cathepsins B, L, and S in this aggressive triple‐negative human breast cancer cell line was confirmed by several studies . The PET images are shown in Figures A and A.…”

Targeting the lysosome in cancer

“…The intercellular release of cathepsins into the extracellular space is of oncogenic character, which has been associated with tumor progression and metastasis in various cancer types. As such, cathepsin inhibitors, including the inhibitors of cathepsins D, B, K, E, S, and L, have been developed for cancer therapy. Although many studies have indicated that cathepsins would be effective targets for cancer drugs, there are currently no cathepsin inhibitors that have advanced to clinical trials in cancer.…”

Cell–matrix interactions: focus on proteoglycan–proteinase interplay and pharmacological targeting in cancer

“…Selective inhibition of cathepsin B leads to limited breast to bone metastasis and reduced invasion of breast cancer cells . Moreover, the inhibition of cathepsin S was reported to reduce the migration of aggressive lung adenocarcinoma and melanoma cells .…”