Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Chem Biol Interact. 2022 Feb 1;353:109811. doi: 10.1016/j.cbi.2022.109811. Epub 2022 Jan 8.
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.
由于其高转移率，胰腺癌将成为全球癌症相关死亡的第二大主要原因。组织蛋白酶（CATs）是各种癌症侵袭性生长的效应物。目前，靶向 CATs 代表了一种有吸引力的策略，可用于治疗 CATs 活性高的高度转移性癌症，如胰腺癌。为了开发更强的抗转移剂，本研究设计了一种新型 CATs 抑制剂 ASPER-29，它是使用 Asperphenamate 衍生物 BBP 作为先导化合物设计的，并研究了其在胰腺癌转移中的治疗潜力。分子对接和酶抑制实验证明，ASPER-29 可以通过与这些酶以经典作用模式结合来抑制 CAT-L 和 CAT-S 的活性。此外，ASPER-29 显著抑制了 PANC-1 和 BxPC-3 细胞中 CAT-L 和 CAT-S 的活性，但对其表达没有影响。通过划痕愈合和 Transwell 室测定法检测了 ASPER-29 的体外抗转移活性。我们发现，ASPER-29 以浓度依赖的方式抑制 PANC-1 和 BxPC-3 细胞的迁移和侵袭。此外，ASPER-29 在小鼠异种移植模型中证实了其体内抗转移作用。H&E 染色和 Ki67 和 CEACAM6 的免疫组化分析证明，ASPER-29 治疗显著阻断了胰腺癌细胞向肺和肝组织的转移。此外，与模型组小鼠相比，ASPER-29 给药小鼠的肺和肝组织中 CAT-L 和 CAT-S 的活性明显受到抑制，这表明 ASPER-29 的阻断转移作用应通过抑制胰腺癌细胞中 CAT-L 和 CAT-S 的活性来介导。总之，我们的研究结果表明，ASPER-29 作为 CAT-L 和 CAT-S 的新型抑制剂，具有明显阻断胰腺癌细胞转移的能力。
