The Current Stage of Cathepsin B Inhibitors As Potential Anticancer Agents

Abstract

Cathepsin B is a lysosomal cysteine peptidase, with an important role in the development and progression of cancer. It is involved in the degradation of extracellular matrix proteins, a process promoting invasion and metastasis of tumor cells and tumor angiogenesis. Cathepsin B is unique among cathepsins in possessing both carboxypeptidase and endopeptidase activities. While the former is associated with its physiological role, the latter is involved in pathological degradation of the extracellular matrix. Its activities are regulated by different means, the most important being its endogenous inhibitors, the cystatins. In cancer this peptidase/inhibitor balance is altered, leading to harmful cathepsin B activity. The latter can be prevented by exogenous inhibitors. They differ in modes of inhibition, size, structure, binding affinity, selectivity, toxicity and bioavailability. In this article, we review the properties and function of endogenous and exogenous cathepsin B inhibitors and indicate their application as possible anticancer agents.

Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis

“…For neoplastic diseases, one of the important roles of cysteine cathepsins is confirmed by accumulating evidence in the progression, invasion, and metastasis of solid tumors and they seem to influence the response of tumor cells to ionizing radiation and cytostatic agents [8–10]. Meanwhile, there is also experimental evidence highlighting that lysosomal cathepsins, in particular cathepsin B, D, and L, may also trigger activation of multiple signaling pathways, which may also result in cell death.…”

Protease Inhibitors in Tick Saliva: The Role of Serpins and Cystatins in Tick-host-Pathogen Interaction

“…Cysteine cathepsins are also implicated in the pathogenesis of psoriasis (Kawada et al, 1997), muscular dystrophy (Takeda et al, 1992), abdominal aortic aneurysm and atherosclerosis (Liu et al, 2006), osteoporosis and rheumatoid arthritis (Yasuda et al, 2005), and acute pancreatitis (Halangk et al, 2000). Relatively recent data are accumulating to suggest that cysteine cathepsins are promising therapeutic targets (Kos et al, 2014; Sudhan and Siemann, 2015). The wide spectrum of tick cystatins with varying specificities provides an opportunity to take advantage of this rich source of natural cathepsin inhibitors.…”

Induction of cathepsin B by the CXCR3 chemokines CXCL9 and CXCL10 in human breast cancer cells

“…CTSB enhances the invasiveness of cancer cells through the degradation of extracellular matrix proteins, by cleavage and inactivation of tissue inhibitors of metalloproteinases, and by disruption of cell-cell junctions. Furthermore, CTSB may affect tumor cell proliferation, migration and apoptosis, and participates in cancer angiogenesis and chemoresistance (5). …”