@article{Xu2025, 
author = {Chao Xu and Zekun Li and Yueying Shan and Chunhua She and Yanfang Yang and Tianxing Zhou and Yongjie Xie and Bo Ni and Chenyang Meng and Guangcong Shen and Boyang Fu and Guannan Sheng and Liangliang Wu and Jinlong Pei and Tiansuo Zhao and Song Gao and Hongwei Wang and Chengqi Deng and Kaiyuan Wang and Antao Chang and Chongbiao Huang and Lei Shi and Shengyu Yang and Jun Yu and Jihui Hao and Xiuchao Wang},
title = {CLT-003 exerts anti-tumor activity in pancreatic cancer by blocking the PI3K/AKT/HIF-1α pathway},
year = {2025},
journal = {Cancer Biology & Medicine},
volume = {22},
number = {12},
pages = {1558-1577},
keywords = {pancreatic ductal adenocarcinoma, PI3K/AKT/mTOR, HIF-1α, malignant progression, CLT-003},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2025.0058},
doi = {10.20892/j.issn.2095-3941.2025.0058},
abstract = {ObjectiveCLT-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.MethodsCell 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.ResultsCLT-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-1α 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-1α expression.ConclusionsThis 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.}
}