Brexpiprazole suppresses cell proliferation and de novo lipogenesis through AMPK/SREBP1 pathway in colorectal cancer.

OBJECTIVE: In the present study, we investigated the role of brexpiprazole on cell proliferation and lipogenesis in colorectal cancer (CRC) and its molecular mechanism. METHODS: The effect of brexpiprazole on CRC cell proliferation was determined by CCK-8, EdU assay, cell clone formation. The flow cytometry was evaluated cell cycle. Differential expression genes (DEGs) were identified by RNA-seq assay after treating HCT116 cells with or without 20 µM brexpiprazole for 24 h. Then, the top 120 DEGs were analyzed by GO and KEGG enrichment analysis. After that, Oil red O staining and the levels of total cholestenone and triglyceride were measured to assess lipogenesis capacity in CRC cells. The related molecules of cell proliferation, lipogenic and AMPK/SREBP1 signal pathways were measured by q-PCR, western blot and immunohistochemical staining. RESULTS: Brexpiprazole remarkably suppressed cell proliferation, lipogenesis, and induced cell cycle arrest in CRC. The underlying mechanisms probably involved the suppression of SREBP1 and the stimulation of AMPK. CONCLUSION: Brexpiprazole inhibited cell proliferation and de novo lipogenesis through AMPK/SREBP1 pathway in CRC.

Brexpiprazole Prevents the Malignant Progression of Human Colorectal Cancer Cells and Increases Its Sensitivity to EGFR Inhibition.

BACKGROUND: Colorectal cancer (CRC) is a major cause of mortality and morbidity. A study proved that brexpiprazole, as a novel dopamine receptor partial agonist, can also prevent CRC cell proliferation. Therefore, clarifying the molecular mechanism of brexpiprazole is vital to developing a novel therapeutic strategy for CRC. METHODS: The effect of brexpiprazole on human colorectal cancer cell proliferation was measured with Cell Counting Kit-8 (CCK-8) kits. Cell migration capability was measured using wound healing and transwell. Cell apoptosis was evaluated with a flow cytometer. Western blots and immunohistochemical staining were used to evaluate protein expression. The effects observed in vitro were also confirmed in xenograft models. RESULTS: Brexpiprazole remarkably inhibited the proliferation, suppressed the migration ability, and induced apoptosis of colorectal cancer cells. Mechanism study showed that brexpiprazole exerted these effects by inhibiting the EGFR pathway. Brexpiprazole enhanced HCT116 cells' sensitivity to cetuximab, and a combination of brexpiprazole and cetuximab inhibited xenograft tumor growth in vivo. CONCLUSIONS: Our finding suggested that brexpiprazole inhibits proliferation, promotes apoptosis, and enhances CRC cells' sensitivity to cetuximab by regulating the EGFR pathway and it might be an efficacious treatment strategy for CRC.

Maintenance of the Expression of c-FLIPL by Hsp70 to Resist Licochalcone A-Induced Anti-Colorectal Cancer Effect through ERK-Mediated Autophagy Induction.

BACKGROUND: The mortality rate of colorectal cancer (CRC) ranks second worldwide. Previous research had indicated that licochalcone A (LA) was a flavonoid in licorice with diverse anticancer effects. We explored the underlying mechanisms of LA-triggered anticancer activity in CRC. METHODS: Thiazolyl Blue (MTT) experiment and EdU staining were utilized to evaluate cell proliferation. Meanwhile, cells were stained by Annexin V/PI to investigate apoptosis through flow cytometry assay. Moreover, expressions of proteins were detected by immunoblotting, and the level of related mRNA was investigated using real-time quantitative PCR. RESULTS: LA selectively suppressed the proliferation and triggered apoptosis of CRC cells. Strikingly, LA induced cytoprotective autophagic activities since the suppression of autophagy significantly strengthened LA-induced cytotoxicity and FLICE inhibitory protein (c-FLIPL) degradation, meanwhile reversing LA-mediated heat shock protein 70 (Hsp70) upregulation. Moreover, autophagy-mediated Hsp70 upregulation resisted LA-induced anticancer effects since the suppression of Hsp70 strengthened LA-triggered cytotoxicity and c-FLIPL degradation. Furthermore, LA greatly activated extracellular signal-regulated protein kinases (ERK) and p38. However, blocking of ERK, but not p38, significantly boosted LA-triggered cell death and c-FLIPL downregulation. Suppression of ERK also reversed LA-mediated autophagic induction. CONCLUSIONS: LA increased Hsp70 expression depending on ERK-mediated autophagy, which protected CRC cells from LA-induced anticancer activities.

Efficacy, safety, and cost-effectiveness analysis of aflibercept in metastatic colorectal cancer: A rapid health technology assessment.

Background: Metastatic colorectal cancer (mCRC) imposes a heavy tumor burden worldwide due to limited availability of therapeutic drugs. Aflibercept, a kind of recombinant protein of the anti-vascular endothelial growth factor (VEGF) family, has been approved in clinical application among mCRC patients since 2012. A comprehensive analysis of the efficacy, safety, and cost-effectiveness of aflibercept in mCRC treatment is necessary. Objective: To evaluate the efficacy, safety, and cost-effectiveness of aflibercept for the treatment of mCRC in order to provide a decision-making reference for the selection of targeted drugs for second-line treatment of mCRC in Hong Kong, Macao, and Taiwan regions of China and the selection of new drugs for medical institutions in these regions. Methods: A systematic retrieve on databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu, as well as relevant websites and databases of health technology assessment including the National Institute of Health and Clinical Optimization, Centre for Evaluation and Communication at the University of York, and the Canadian Agency for Medicines and Health Technology, was conducted. The literature was screened according to the inclusion and exclusion criteria, and data were extracted and analyzed by two authors, while the quality of the literature was assessed. Results: Finally, we included two HTA reports, 11 systematic reviews/meta-analyses, and two cost-effectiveness studies in the rapid health technology assessment. For mCRC patients receiving second-line treatment, aflibercept combined with FOLFIRI significantly increased progression-free survival (PFS) and overall survival (OS) and the objective response rate (ORR) also improved, compared with folinic acid + fluorouracil + irinotecan (FOLFIRI). In terms of safety, mCRC patients who received aflibercept combined with FOLFIRI therapy had a higher incidence of grade 3-4 adverse events than those who received FOLFIRI alone, including anti-VEGF-related adverse events (hypertension, hemorrhagic events, and proteinuria) and chemotherapy-related adverse events (diarrhea, weakness, stomatitis, hand-foot syndrome, neutropenia, and thrombocytopenia). In terms of cost-effectiveness, two economic studies conducted in the United Kingdom and Japan, respectively, found that compared with FOLFIRI, aflibercept combined with FOLFIRI had no cost-effectiveness advantage in mCRC patients receiving second-line treatment. Conclusion: Compared with FOLFIRI treatment, aflibercept combined with FOLFIRI for the second-line treatment of mCRC patients has better efficacy, worse safety, and is not cost-effective. More high-quality clinical studies are required for further exploration of aflibercept's clinical value. Medical institutions in Hong Kong, Macao, and Taiwan regions of China should be cautious when using or introducing aflibercept plus FOLFIRI as a mCRC treatment.

Anchoring Metallic MoS2 Quantum Dots over MWCNTs for Highly Sensitive Detection of Postharvest Fungicide in Traditional Chinese Medicines.

Carbendazim, a very common contamination to the traditional Chinese medicines (TCMs), has posed serious threat to the environment and human health. However, sensitive and selective detection of carbendazim (MBC) in the TCMs is a big challenge for their complex chemical constituents. In this work, a 0D/1D nanohybrid was developed by anchoring 1T-phased MoS2 quantum dots (QDs) over multiwall carbon nanotubes (MWCNTs) via a facile assembly method. High-resolution transmission electron microscopy (HRTEM), Raman spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis (TGA) together with EIS reveal that the 1T-phased QDs can anchor over MWCNTs via van der Waals forces, and the anchoring improves the nanohybrid surface area and conductivity. Therefore, the electrochemical sensor fabricated based on the MoS2 QDs@MWCNT nanohybrid shows excellent catalytic activity to MBC oxidation. Under optimized conditions, the sensor presents a linear voltammetry response to MBC concentration from 0.04 to 1.00 µmol·L-1, a low detection limit of 2.6 × 10-8 mol·L-1, as well as high selectivity, good reproducibility, and long-term stability. Moreover, the sensor has been successfully employed to determine MBC in two typical TCMs and the obtained recoveries are in good accordance with the results achieved by HPLC, showing that the constructed sensor plate holds great practical application in MBC analysis with complex matrix.