Article ; Online: Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer.
European journal of pharmacology
2024 Volume 969, Page(s) 176431
Abstract: Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been ... ...
Abstract | Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been determined. In our study, a new nonradioactive and highly sensitive method for analysing nab-paclitaxel transcytosis was established. Based on these methods, we found that hypoxia significantly enhanced the autophagic degradation of CAV1 and therefore attenuated caveolae-mediated nab-paclitaxel transcytosis across endothelial cells (ECs). In a proof-of-concept experiment, higher levels of CAV1, accompanied by lower levels of LC3B, were observed in the vascular endothelium of pancreatic cancer tissues collected from patients who showed a good response to nab-paclitaxel compared with those from patients who showed a poor response to nab-paclitaxel. Furthermore, both in vivo and in vitro studies confirmed that suppressing the autophagic degradation of CAV1 via EC-specific ATG5 knockdown or hydroxychloroquine sulfate (HCQ) treatment significantly enhanced nab-paclitaxel translocation across the endothelial barrier into pancreatic cancer cells and amplified the inhibitory effect of nab-paclitaxel on pancreatic tumour growth. The stimulation of CAV1 expression by EC-specific overexpression of exogenous CAV1 or administration of gemcitabine hydrochloride (GE) had the same effect. These results demonstrated that suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic cancer. |
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MeSH term(s) | Humans ; Deoxycytidine/therapeutic use ; Endothelial Cells/pathology ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Paclitaxel/pharmacology ; Albumins/pharmacology ; Transcytosis ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use |
Chemical Substances | Deoxycytidine (0W860991D6) ; Paclitaxel (P88XT4IS4D) ; Albumins |
Language | English |
Publishing date | 2024-02-22 |
Publishing country | Netherlands |
Document type | Journal Article |
ZDB-ID | 80121-5 |
ISSN | 1879-0712 ; 0014-2999 |
ISSN (online) | 1879-0712 |
ISSN | 0014-2999 |
DOI | 10.1016/j.ejphar.2024.176431 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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