Chemoresistance is the main cause of poor prognosis in
colorectal cancer (CRC).
Nicotinamide N‑methyltransferase (
NNMT) is a metabolic
enzyme that is upregulated in various
tumor types. It has been reported that
NNMT inhibits apoptosis and enhances resistance to 5‑fluorouracil (5‑Fu) 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 4‑hydroxy‑3‑methoxybenzaldehyde, 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 NNMT‑induced resistance to 5‑Fu in CRC. Lentiviral vectors of
short hairpin RNA and
small interfering RNA were transfected into HT‑29 cells to construct NNMT‑knockdown HT‑29 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 HT‑29 cell lines.
Vanillin was able to reverse NNMT‑induced increased cell proliferation, decreased cell apoptosis and resistance to 5‑Fu by inhibiting
NNMT expression. Furthermore, it increased cell apoptosis by activating the ASK1‑p38 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 5‑Fu 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 NNMT‑induced resistance to 5‑Fu in human CRC
therapy with few side effects.