Application of G-quadruplex targets in gastrointestinal cancers: Advancements, challenges and prospects.

Genomic instability and inflammation are considered to be two enabling characteristics that support cancer development and progression. G-quadruplex structure is a key element that contributes to genomic instability and inflammation. G-quadruplexes were once regarded as simply an obstacle that can block the transcription of oncogenes. A ligand targeting G-quadruplexes was found to have anticancer activity, making G-quadruplexes potential anticancer targets. However, further investigation has revealed that G-quadruplexes are widely distributed throughout the human genome and have many functions, such as regulating DNA replication, DNA repair, transcription, translation, epigenetics, and inflammatory response. G-quadruplexes play double regulatory roles in transcription and translation. In this review, we focus on G-quadruplexes as novel targets for the treatment of gastrointestinal cancers. We summarize the application basis of G-quadruplexes in gastrointestinal cancers, including their distribution sites, structural characteristics, and physiological functions. We describe the current status of applications for the treatment of esophageal cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, and gastrointestinal stromal tumors, as well as the associated challenges. Finally, we review the prospective clinical applications of G-quadruplex targets, providing references for targeted treatment strategies in gastrointestinal cancers.

The bound polyphenols of foxtail millet (Setaria italica) inner shell inhibit breast cancer by promoting lipid accumulation-induced autophagic death.

Foxtail millet is a traditional excellent crop with high nutritional value in the world, belong to cereals. The bran of foxtail millet is rich in polyphenol that has antioxidant, anti-inflammatory, and anti-tumorigenic effects. Previously, we extracted bound polyphenols from the inner shell of foxtail millet bran (BPIS). Here, we report that BPIS specifically induced breast cancer cell death and elevated the autophagy level simultaneously. The addition of an autophagy inhibitor blocked BPIS-induced breast cancer cell death, indicating that excessive autophagy induced cell death. Furthermore, oil red O and BODIPY staining also confirmed that lipids, which are important inducers of autophagy, accumulated in breast cancer cells treated with BPIS. Lipidomics research revealed that glycerophospholipids were the main accumulated lipids induced by BPIS. Further study showed that elevated PCYT1A expression was responsible for glycerophospholipid accumulation, and BPIS contained ferulic acid and p-coumaric acid, which induced PCYT1A expression and breast cancer cell death. Collectively, our results revealed that BPIS resulted in autophagic death by enhancing lipid accumulation in breast cancer cells, and BPIS contains ferulic acid and p-coumaric acid, which provided new insights into developing nutraceuticals and drugs for breast cancer patients.

Transplantation of mesenchymal stem cells modulated Cx43 and Cx45 expression in rats with myocardial infarction.

At present, little is known about the influence of mesenchymal stem cell (MSC) transplantation on connexin43 (Cx43) and connexin45 (Cx45) remodeling in the ischemic heart. In this study, we investigated the effect of MSC transplantation on Cx43 and Cx45 remodeling in the ischemic heart. Wistar rats were subjected to left anterior descending artery ligation to induce myocardial infarction (MI) and then randomly allocated to receive an intramyocardial injection of PBS (MI group) or 5-azacytidine-induced MSCs (MSCs group). Histological examination and western blotting were performed 4 weeks after cell transplantation. We found that the MSCs exhibited plasticity by differentiating into cardiomyocyte-like cells. Gap junction remodeling after MI was characterized by a decrease in Cx43 expression and an increase in Cx45 expression. MSC transplantation modulated the MI-induced abnormalities by up-regulating Cx43 and down-regulating Cx45 expression. MSCs exhibited plasticity by differentiating into cardiomyocyte-like cells and modulated abnormal Cx43 and Cx45 remodeling following MI.

Spectroscopic investigation of the interaction between G-quadruplex of KRAS promoter sequence and three isoquinoline alkaloids.

KRAS promoter can form G-quadruplex structure and regulate gene transcription. The drugs which can bind with G-quadruplex of KRAS promoter may be potential remedy for treatment of cancers associated with KRAS mutation. The interaction mechanism between the G-quadruplex of KRAS promoter and three isoquinoline alkaloids (jatrorrhizine, berberine and sanguinarine) has been investigated by UV-visible, fluorescence and circular dichroism spectroscopic methods. The results showed that the three alkaloids can form complexes with G-quadruplex KRAS promoter with the molecular ratio of 1:1, and the binding constants were (0.90±0.16)×106Lmol-1, (0.93±0.21)×106Lmol-1 and (1.16±0.45)×106Lmol-1 for jatrorrhizine, berberine and sanguinarine. The absorption spectra, KI quenching and fluorescence anisotropy and polarization studies suggested jatrorrhizine and berberine interacted with G-quadruplex by not only end-stacking binding mode but also grooves or loops binding mode, while sanguinarine by end-stacking binding mode. Sanguinarine was more beneficial to maintain the stability and parallel conformation of KRAS promoter G-quadruplex. MTT assay was performed to evaluate antiproliferation effects of the three isoquinoline alkaloids on SW620 cells, and the antiproliferation effects of the three alkaloids were sanguinarine > berberine > jatrorrhizine. All the three alkaloids can bind with KRAS promoter G-quadruplex, and sanguinarine had the better binding property and antiproliferation effects on SW620 cells. The results obtained are meaningful to explore potential reagents targeting the parallel G-quadruplex structure of KRAS promoter for gene theraphy of colorectal carcinomas.

Evidence of different G-quadruplex DNA binding with biogenic polyamines probed by electrospray ionization-quadrupole time of flight mass spectrometry, circular dichroism and atomic force microscopy.

The binding properties of five G-quadruplex oligonucleotides (humtel24, k-ras32, c-myc22, c-kit1 and c-kit2) with polyamines have been investigated by electrospray ionization-quadrupole time of flight mass spectrometry, circular dichroism, melting temperature, atomic force microscopy (AFM) and molecular simulation. The MS results demonstrated that the polyamines and G-quadruplex DNA can form complexes with high affinity, and one molecule of G-quadruplex DNA can combine several molecules (1-5) of polyamines. The binding affinities of the polyamines to DNA were in the order of spermine > spermidine > putrescine. After binding with polyamines, the conformations of the G-quadruplex DNA were significantly changed, and spermine can induce the configurations of k-ras32 and c-kit1 to deviate from their G-quadruplex structures at high concentrations. In the presence of K(+), the conformations of G-quadruplex DNA were stabilized, while polyamines can also induced alterations of their configurations. Melting temperature experiments suggested that the Tm of the DNA-polyamine complexes obviously increased both in the absence and presence of K(+). The AFM results indicated that polyamines can induce aggregation of G-quadruplex DNA. Above results illustrated that the polyamines bound with the phosphate backbone and the base-pairs of G-quadruplex structures. Combining with the molecular simulation, the binding mode of the G-quadruplex DNA and polyamines were discussed. The results obtained would be beneficial for understanding the biological and physiological functions of polyamines and provide useful information for development of antitumor drugs.