Synthesis, characterization, and evaluation of a novel inhibitor of WNT/β-catenin signaling pathway

Abstract

BackgroundWnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo.ResultsCell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43 ± 1.99, 6.95 ± 0.24, and 7.62 ± 1.31 μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100 mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound.ConclusionsOur data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/β-catenin signalling

“…BHX, a novel low molecular weight pyrazoline derivative, was previously synthesized in our laboratory. We have demonstrated that BHX exhibits cytotoxic effects in multiple solid tumour cell lines, including A549, HT29, and MGC803 15 . In the present study, we have further verified that BHX suppresses not only cell viability but also cell migration and invasion, and induces cell cycle G1 phase arrest.…”

“…PVDF membranes were supplied by Millipore (Billerica, MA, USA). BHX was synthesized as previously described 15 .…”

“…Previously, our studies showed that BHX exerted potent in vitro and in vivo anti-tumour activity against various solid tumours. BHX inhibited tumour cell proliferation, induced cell cycle arrest and apoptosis, decreased β-catenin protein levels, and increased E-cadherin expression 15 . However, the effects of BHX on breast cancer cells, and the specific molecules targeted by BHX responsible for its anti-tumour activity, are unknown.…”

miR‑138 modulates prostate cancer cell invasion and migration via Wnt/β‑catenin pathway

“…These results indicate that drugs and inhibitors targeting this pathway may have clinical potential in the treatment of prostate cancer. Various inhibitors are currently at developmental stages (29)(30)(31)(32), however require further evaluation regarding their role in prostate cancer.…”

Apoptosis induction in K562 human myelogenous leukaemia cells is connected to the modulation of Wnt/β‐catenin signalling by BHX, a novel pyrazoline derivative

“…The novel pyrazoline derivative, N ‐(4‐hydroxybenzyl)‐1,3,4‐triphenyl ‐4,5‐dihydro‐1 H ‐pyrazole‐5‐carboxamide (BHX), designed and synthesized previously, has been described to block the canonical Wnt/β‐catenin signalling pathway, and has been reported to exhibit cytotoxic effects in multiple solid tumour cell lines . However, the anti‐proliferative effects of BHX on leukaemia cells have not been previously investigated.…”