ASPER-29 suppresses the metastasis of pancreatic cancer cells by dual inhibition of cathepsin-L and cathepsin-S.

Abstract

Pancreatic cancer will be the second leading cause of cancer-related mortality worldwide due to its high rate of metastasis. Cathepsins (CATs) are effectors of invasive growth in various cancers. Currently, targeting CATs represents an attractive strategy for the treatment of highly metastatic cancers with high CATs activity, such as pancreatic cancer. To develop a stronger antimetastatic agent, ASPER-29, a novel inhibitor of CATs designed by using the asperphenamate derivative BBP as a lead compound, was synthesized, and its therapeutic potential in pancreatic cancer metastasis was investigated in this study. Molecular docking and enzyme inhibition assays proved that ASPER-29 can inhibit the activity of CAT-L and CAT-S by binding with these enzymes in classical action modes. Furthermore, ASPER-29 significantly inhibited the activity of CAT-L and CAT-S but had no effect on their expression in PANC-1 and BxPC-3 cells. The in vitro antimetastatic activities of ASPER-29 were examined by wound healing and Transwell chamber assays. We found that ASPER-29 inhibited the migration and invasion of PANC-1 and BxPC-3 cells in a concentration-dependent manner. Moreover, the in vivo antimetastatic effects of ASPER-29 were confirmed in a mouse xenotransplantation model. H&E staining and immunohistochemistry assays of Ki67 and CEACAM6 proved that ASPER-29 treatment significantly blocked the metastasis of pancreatic cancer cells to lung and liver tissues. Additionally, the activity of both CAT-L and CAT-S was markedly inhibited in the lung and liver tissues of ASPER-29-administered mice compared with the mice in the model group, suggesting that the metastasis-blocking effect of ASPER-29 should be mediated via inhibition of the activity of CAT-L and CAT-S in pancreatic cancer cells. Together, our results demonstrated that ASPER-29, as a novel inhibitor of CAT-L and CAT-S, possessed the evident ability to block the metastasis of pancreatic cancer cells.

• Authors: Lei Yuan, Juanping Zhao, Songkun Zhao, Tianyi Dong, Ruitong Dong, Dongyue Liu, Enlong Ma, Yanchun Li
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 353 Pg. 109811 (Feb 01 2022) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 35016848 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Antigens, CD
• Antineoplastic Agents
• Cell Adhesion Molecules
• GPI-Linked Proteins
• Gm5893 protein, mouse
• Protease Inhibitors
• Cathepsins
• Cathepsin L
• cathepsin S

Topics

• Animals
• Antigens, CD (metabolism)
• Antineoplastic Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Binding Sites
• Cathepsin L (antagonists & inhibitors, metabolism)
• Cathepsins (antagonists & inhibitors, metabolism)
• Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Female
• GPI-Linked Proteins (antagonists & inhibitors, metabolism)
• Humans
• Liver (metabolism, pathology)
• Lung (metabolism, pathology)
• Mice
• Mice, Nude
• Molecular Docking Simulation
• Neoplasm Metastasis
• Pancreatic Neoplasms (drug therapy, pathology)
• Protease Inhibitors (chemistry, metabolism, pharmacology, therapeutic use)
• Transplantation, Heterologous