Resveratrol, extracted from Chinese herbal medicine Polygonum cuspidatum, is known to inhibit invasion and metastasis of human colorectal cancer (CRC), in which long non-coding Metastasis Associated Lung Adenocarcinoma Transcript 1 (RNA-MALAT1) also plays an important role. Using MALAT1 lentiviral shRNA and over-expression constructs in CRC derived cell lines, LoVo and HCT116, we demonstrated that the anti-tumor effects of resveratrol on CRC are through inhibiting Wnt/β-catenin signaling, thus the expression of its target genes such as c-Myc, MMP-7, as well as the expression of MALAT1. In detail, resveratrol down-regulates MALAT1, resulting in decreased nuclear localization of β-catenin thus attenuated Wnt/β-catenin signaling, which leads to the inhibition of CRC invasion and metastasis. This finding of ours surely provides important pre-clinical evidence supporting future use of resveratrol in prevention and treatment of CRC.
The
use of peptidomimetic scaffolds is a promising strategy for
the inhibition of protein–protein interactions (PPIs). Herein,
we demonstrate that sulfono-γ-AApeptides can be rationally designed
to mimic the p53 α-helix and inhibit p53–MDM2 PPIs. The
best inhibitor, with K
d and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is
among the most potent unnatural peptidomimetic inhibitors disrupting
the p53–MDM2/MDMX interaction. Using fluorescence polarization
assays, circular dichroism, nuclear magnetic resonance spectroscopy,
and computational simulations, we demonstrate that sulfono-γ-AApeptides
adopt helical structures resembling p53 and competitively inhibit
the p53–MDM2 interaction by binding to the hydrophobic cleft
of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed
promising cellular activity by enhancing p53 transcriptional activity
and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides
exhibited remarkable resistance to proteolysis, augmenting their biological
potential. Our results suggest that sulfono-γ-AApeptides are
a new class of unnatural helical foldamers that disrupt PPIs.
BackgroundZuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro.MethodsWe tested the dose–response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression.ResultsWe found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells.ConclusionsOur study has provided the first direct evidence that ZJW reverses drug-resistance in human colorectal cancer by blocking the PI3K/Akt/NF-κB signaling pathway, and could be considered as a useful drug for cancer therapy.
β-arrestins are a family of adaptor proteins that regulate the signaling and trafficking of various G protein-coupled receptors (GPCRs). They consist of β-arrestin1 and β-arrestin2 and are considered to be scaffolding proteins. β-arrestins regulate cell proliferation, promote cell invasion and migration, transmit anti-apoptotic survival signals and affect other characteristics of tumors, including tumor growth rate, angiogenesis, drug resistance, invasion and metastatic potential. It has been demonstrated that β-arrestins serve roles in various physiological and pathological processes and exhibit a similar function to GPCRs. β-arrestins serve primary roles in cancer invasion and metastasis via various signaling pathways. The present review assessed the function and mechanism of β-arrestins in cancer invasion and metastasis via multiple signaling pathways, including mitogen-activated protein kinase/extracellular signal regulated kinase, Wnt/β-catenin, nuclear factor-κB and phosphoinositide-3 kinase/Akt.
Antibiotic
resistance has emerged as one of the biggest public
health concerns all over the world. In an effort to combat bacterial
infections, a series of imidazolidine-4-one derivatives with potent
and broad-spectrum antibacterial activity and low rates of drug resistance
were developed by mimicking the salient physiochemical features of
host defense peptides. These small molecules displayed potent activity
against both Gram-negative and Gram-positive bacteria including several
multidrug-resistant bacteria strains. Meanwhile, time–kill
kinetics and drug resistance studies suggested that the most potent
compound 3 could not only eliminate the bacteria rapidly
but also exhibit a low probability of drug resistance in MRSA over
many passages. Further mechanistic studies suggested that 3 eradicated bacterial pathogens by disintegrating membranes of both
Gram-negative and Gram-positive bacteria. Together with their small
molecular weight and low production cost compared with HDPs, these
imidazolidine-4-one compounds may be developed into a new generation
of antibiotic therapeutics combating emergent drug resistance.
Evodiamine (Evo), extracted from the Chinese herbal medicine Evodia rutaecarpa, has cytotoxic effects on different types of human cancer cells. However, its effects on drug resistance and their molecular mechanism and therapeutic target in colorectal cancer are not well understood. In the present study, we observed that Evo inhibited cell growth and induced apoptosis in adose-and time-dependent manner in HCT-116/L-OHP cells. Moreover, Evo treatment reduced Rhodamine 123 accumulation and ATPase activity in HCT-116/L-OHP cells, indicating that Evo decreased the efflux function in HCT-116/L-OHP cells. Interestingly, phosphorylation of NF-κB pathway, particularly p50/p65, was also inhibited by Evo treatment. Furthermore the effect of Evo in reversing drug resistance and suppressing phosphorylation of NF-κB pathway were attenuated after treatment with the NF-κB activator (LPS). Additionally, Evo inhibited the tumor growth in a colorectal MDR cancer xenograft model and down regulated p-NF-κB level in vivo. Our study provided the first direct evidence that Evo can attenuate multidrug resistance by blocking p-NF-κB signaling pathway in human colorectal cancer. Evo could be a potential candidate for cancer chemotherapy.
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