Andrographis overcomes 5-fluorouracil-associated chemoresistance through inhibition of DKK1 in colorectal cancer.
Carcinogenesis
; 42(6): 814-825, 2021 06 21.
Article
en En
| MEDLINE
| ID: mdl-33822896
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Extractos Vegetales
/
Neoplasias Colorrectales
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Regulación Neoplásica de la Expresión Génica
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Resistencia a Antineoplásicos
/
Andrographis
/
Péptidos y Proteínas de Señalización Intercelular
/
Fluorouracilo
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Carcinogenesis
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos