Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities...Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities.Nevertheless,the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated.Methods:Cell proliferation and apoptosis were detected using CCK-8,real-time cell analysis(RTCA),EdU,and flow cytometric assays.Cellular mobility and invasive capacity were detected using wound-healing,Transwell,and cell motility assays.Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models.The antitumor effects of CLT-003 were evaluated using patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.Results:CLT-003 significantly inhibited cellular proliferation,enhanced cellular apoptosis,and attenuated cellular invasion and migration of pancreatic cancer cells.Mechanistically,CLT-003 suppressed the translation of HIF-1a by inhibiting the PI3K/AKT/mTOR signaling pathway.In the mouse tumor models,CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors.Moreover,the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1a expression.Conclusions:This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82472973,82030092,82273362,82272680,and 82103006)the National Key Research and Development Program of China(Grant No.2021YFA1201100)+2 种基金the Tianjin Natural Science Foundation(Grant Nos.19JCJQJC63100 and 22JCQNJC00100)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2022KJ221)the Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-009A).
文摘Objective:CLT-003 is a novel phenylphthalimide derivative encapsulated in poly(lactate-glycolic acid)copolymer nanoparticles using nanotechnology techniques.CLT-003 possesses anti-angiogenetic and antitumor activities.Nevertheless,the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated.Methods:Cell proliferation and apoptosis were detected using CCK-8,real-time cell analysis(RTCA),EdU,and flow cytometric assays.Cellular mobility and invasive capacity were detected using wound-healing,Transwell,and cell motility assays.Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models.The antitumor effects of CLT-003 were evaluated using patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.Results:CLT-003 significantly inhibited cellular proliferation,enhanced cellular apoptosis,and attenuated cellular invasion and migration of pancreatic cancer cells.Mechanistically,CLT-003 suppressed the translation of HIF-1a by inhibiting the PI3K/AKT/mTOR signaling pathway.In the mouse tumor models,CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors.Moreover,the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1a expression.Conclusions:This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.
