Dataset Information

Synergistic activity of simvastatin and irinotecan chemotherapy against glioblastoma converges on TGF-β

ABSTRACT: Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a dismal prognosis and inevitable recurrence after standard-of-care therapy. This warrants the need for rapidly translatable, more effective GBM treatments. We have therefore investigated the therapeutic potential of a novel combination of the repurposed drug simvastatin with irinotecan chemotherapy (CPT-11).

ORGANISM(S): Homo sapiens

PROVIDER: GSE297728 | GEO | 2026/05/20

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies about complex mixtures effects. PHY906 is a long used four herb TCM formula employed as adjuvant to relieve side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when PHY906 was combined. Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of Irinotecan by PHY-906 in a well-characterized pre-clinical model; PHY-906 and Irinotecan were administered orally to female BDF-1 mice bearing subcutaneous Colon 38 tumors. We observed that 1) individually PHY-906 and Irinotecan induce distinct alterations in tumor, liver and spleen; 2) PHY-906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of Irinotecan, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection. Most importantly, PHY-906 together with Irinotecan triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response. Four groups of BDF-1 mice bearing colon 38 tumors were treated with Phosphate Buffered Saline (PBS) (n=10), PHY-906 (n=10), Irinotecan (CPT-11, Camptosar(TM)) (n=10) or the combination PHY-906 and Irinotecan (n=10). Tumor (38 samples), spleen (38 samples), and liver (35 samples) tissues were removed and frozen for total RNA isolation and subsequent microarray hybridization. There were a total of 111 samples representing 12 treated tissue groups with 8 to 10 biological replicates each. A reference sample was generated from a pool of mixed normal mouse tissue.

Project description:<p>Irinotecan (CPT-11) is widely used for colorectal cancer treatment, with delayed-onset diarrhea as its primary side effect. Xiao-Chai-Hu-Tang (XCHT) has been clinically observed to alleviate diarrhea, but its mechanisms remain unclear. This study aimed to explore the underlying regulatory mechanisms through which XCHT alleviated CPT-11-induced diarrhea. The chemical components of XCHT were detected using UHPLC-Q-Exactive Orbitrap-MS, and 12 active components were quantified via UHPLC-QQQ-MS/MS to ensure quality stability. CPT-11-induced diarrheal mice were established to evaluate the effects of XCHT. Differential metabolites in liver and intestinal tissues among control, CPT-11, and XCHT mice was analyzed by metabolomics, followed by molecular network analysis using IPA. The bile acids were quantified by using the UHPLC-QQQ-MS/MS method. Proteomics of colon tissues identified differentially expressed proteins, with functional enrichment conducted via GO and KEGG. Western blot and flow cytometry were used to validate potential biopathway. XCHT primarily contained flavonoids, carbohydrates and glycosides, and terpenoids. Twelve active components remained stable throughout the experiment. XCHT significantly improved diarrhea symptoms. Metabolomics revealed 133 and 72 differential metabolites in the liver and intestine, respectively, and linked to bile acid metabolism. Further targeted bile acid analysis revealed that CPT-11 reduced hepatic bile acid synthesis and uptake, but increased biliary excretion. Significantly elevated bile acid levels were observed in the gallbladder of CPT-11-treated mice. Furthermore, intestinal bile acid reabsorption was impaired with an 81% decrease in total bile acids and reduced uptake/efflux, resulting in a 56% decline in circulatory bile acids, and 40% increase in colonic accumulation. Proteomics identified 86 differentially expressed proteins in colon tissues, with significant enrichment in ‘Focal adhesion’. Integrated analysis and validation studies suggested the TGR5-FAK-RhoA/ROCK signaling axis as the crucial pathway through which XCHT alleviated diarrhea. These findings provide novel insights into the pharmacological mechanisms of XCHT and suggest potential therapeutic strategies targeting bile acid metabolism for chemotherapy-induced diarrhea.</p>

Dataset Information

Synergistic activity of simvastatin and irinotecan chemotherapy against glioblastoma converges on TGF-β

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets