Andrographis overcomes 5-fluorouracil-associated chemoresistance through inhibition of DKK1 in colorectal cancer.
Andrographis
/ chemistry
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Colorectal Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
Fluorouracil
/ pharmacology
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Intercellular Signaling Peptides and Proteins
/ chemistry
Male
Mice
Mice, Nude
Plant Extracts
/ pharmacology
Prognosis
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Carcinogenesis
ISSN: 1460-2180
Titre abrégé: Carcinogenesis
Pays: England
ID NLM: 8008055
Informations de publication
Date de publication:
21 06 2021
21 06 2021
Historique:
received:
24
02
2021
revised:
21
03
2021
accepted:
01
04
2021
pubmed:
7
4
2021
medline:
23
11
2021
entrez:
6
4
2021
Statut:
ppublish
Résumé
Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths in the USA. 5-Fluorouracil (5FU)-based chemotherapeutic drug remains a mainstay of CRC treatment. Unfortunately, ~50-60% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU-resistant (5FUR) CRC cells and observed that combined treatment with andrographis-5FU in 5FUR cells exhibited superior effect on cell viability, proliferation, and colony formation capacity compared with individual treatments (P < 0.001). To identify key genes and pathways responsible for 5FU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, Dickkopf-1 (DKK1) overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (P < 0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of 5FU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC.
Identifiants
pubmed: 33822896
pii: 6211334
doi: 10.1093/carcin/bgab027
pmc: PMC8215595
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Biomarkers, Tumor
0
DKK1 protein, human
0
Intercellular Signaling Peptides and Proteins
0
Plant Extracts
0
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
814-825Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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