Vanillin downregulates NNMT and attenuates NNMTrelated resistance to 5fluorouracil via ROSinduced cell apoptosis in colorectal cancer cells.
Oncol Rep
; 45(6)2021 Jun.
Article
en En
| MEDLINE
| ID: mdl-33907844
ABSTRACT
Chemoresistance is the main cause of poor prognosis in colorectal cancer (CRC). Nicotinamide Nmethyltransferase (NNMT) is a metabolic enzyme that is upregulated in various tumor types. It has been reported that NNMT inhibits apoptosis and enhances resistance to 5fluorouracil (5Fu) via inhibition of the apoptosis signal regulating kinase 1 (ASK1)p38 MAPK pathway in CRC cells. A natural product library was screened, and it was found that vanillin, also known as 4hydroxy3methoxybenzaldehyde, a plant secondary metabolite found in several essential plant oils, mainly Vanilla planifolia, Vanilla tahitensis, and Vanilla pompon, may be a promising anticancer compound targeted to NNMT. The aim of the present study was to explore the effect of vanillin on promoting apoptosis and attenuating NNMTinduced resistance to 5Fu in CRC. Lentiviral vectors of short hairpin RNA and small interfering RNA were transfected into HT29 cells to construct NNMTknockdown HT29 cell lines. Vectors containing an open reading frame of NNMT were stably transfected into SW480 cells to induce NNMT overexpression in SW480 cell lines. Vanillin was found to inhibit the mRNA and protein expression levels of NNMT following the inhibition of NNMT activity in HT29 cell lines. Vanillin was able to reverse NNMTinduced increased cell proliferation, decreased cell apoptosis and resistance to 5Fu by inhibiting NNMT expression. Furthermore, it increased cell apoptosis by activating the ASK1p38 MAPK pathway, which could be inhibited by NNMT. In addition, vanillin increased cell apoptosis by promoting mitochondrial damage and reactive oxygen species. In vivo, the combination of vanillin with 5Fu yielded a notable synergy in inhibiting tumor growth and inducing apoptosis. Considering that vanillin is an important flavor and aromatic component used in foods worldwide, vanillin is deemed to be a promising anticancer candidate by inhibiting NNMT and may attenuate NNMTinduced resistance to 5Fu in human CRC therapy with few side effects.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Benzaldehídos
/
Neoplasias Colorrectales
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Nicotinamida N-Metiltransferasa
/
Fluorouracilo
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article