In 2019, streptoglutarimide H (SGH) was characterized as a new glutarimide from the secondary metabolites produced by a marine-derived actinomyceteStreptomycessp. ZZ741 and shown to have in vitro antiglioma activity. However, the antiproliferative activity and potential mechanism of SGH against lung cancer cells have not yet been characterized. This study demonstrated that SGH significantly inhibited the proliferation of different lung cancer cells. In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis-related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28. Potent anticancer activity and multiple mechanisms indicated SGH to be a novel antitumor compound against lung cancer cells.Keywords:Streptoglutarimide H;lung cancer cells;antiproliferative activity;cell cycle block;glycolysis;USP28;c-Myc
Background Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics.Methods The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis.Results Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants.Conclusion sRhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.
Qianqian Wang,Yuwei Liu,Yuanyuan Zheng,Di Chen,Ya Xie,Nian Shi
This work presents an advanced automated monolithic C18 pipette-tip solid-phase extraction (PT-SPE) method seamlessly integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for precise therapeutic drug monitoring of eleven tyrosine kinase inhibitors (TKIs) in biological samples. Commercially available MonoTip C18 columns facilitate superior extraction efficiency and selectivity from complex biological matrices owing to their large surface areas and enhanced mass transfer capabilities. The sample preparation process, conducted by aspirating and dispensing solutions using a pipettor, completes the overall extraction process within 3 min. The method validation demonstrated excellent linearity within the range of 0.2/0.5/0.8 to 200 ng/mL, with detection limits ranging from 0.049 to 0.206 ng/mL. The method exhibited outstanding accuracy and precision, with intraday relative recovery rates ranging from 96.3 % to 115.0 % and interday recovery rates ranging from 95.0 % to 115.7 %, with coefficient of variation values consistently below 13.8 %. The proposed method is distinguished by its exceptional efficiency, reduced solvent use, enhanced environmental sustainability, and streamlined automation—key advantages in the realm of clinical therapeutic drug monitoring of TKIs. Overall, the MonoTip C18 PT-SPE technique, coupled with LC-MS/MS, offers a formidable, eco-friendly, and effective strategy for the TDM of TKIs, marking a significant advancement in the field.
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