Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer.
Acetylcysteine
/ administration & dosage
Adenocarcinoma, Mucinous
/ drug therapy
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Appendiceal Neoplasms
/ drug therapy
Bromelains
/ administration & dosage
Drug Resistance, Neoplasm
/ drug effects
Humans
Mice, Nude
Mucus
/ drug effects
Peritoneal Neoplasms
/ drug therapy
Rats, Nude
Tissue Culture Techniques
/ methods
Xenograft Model Antitumor Assays
Mice
Rats
Journal
Translational research : the journal of laboratory and clinical medicine
ISSN: 1878-1810
Titre abrégé: Transl Res
Pays: United States
ID NLM: 101280339
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
27
04
2020
revised:
10
10
2020
accepted:
19
10
2020
pubmed:
10
11
2020
medline:
6
8
2021
entrez:
9
11
2020
Statut:
ppublish
Résumé
Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.
Identifiants
pubmed: 33164812
pii: S1931-5244(20)30246-2
doi: 10.1016/j.trsl.2020.10.005
pmc: PMC7867596
mid: NIHMS1640071
pii:
doi:
Substances chimiques
Bromelains
9001-00-7
Acetylcysteine
WYQ7N0BPYC
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100-114Subventions
Organisme : NCI NIH HHS
ID : P30 CA047904
Pays : United States
Organisme : NIBIB NIH HHS
ID : R13 EB033695
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA241004
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211241
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
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