Exploring the therapeutic potential of "Zhi-Zhen" formula for oxaliplatin resistance in colorectal cancer: an integrated study combining UPLC-QTOF-MS/MS, bioinformatics, network pharmacology, and experimental validation.
Yongjing Li, Ke Chen, Qin Li, Qiaoli Liu, Huijie Han, Hui Liu, Songpo Wang
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引用次数: 0
Abstract
Background: Chemoresistance is a critical factor compromising the survival of patients with colorectal cancer (CRC). The "Zhi-Zhen" formula (ZZF), a traditional prescription developed by Chinese national medicine masters, has been extensively used in clinical practice to treat gastrointestinal cancer. Notably, ZZF has the potential to enhance tumor sensitivity to chemotherapy. Although previous in vitro studies have demonstrated the efficacy of ZZF in overcoming chemoresistance in colorectal cancer (CRC), its precise molecular mechanisms remain poorly understood.
Materials and methods: We used an integrated approach of bioinformatics and network pharmacology to predict the potential active ingredients and targets of ZZF in alleviating chemoresistance. The top five active ingredients identified by degree in the network analysis were validated using mass spectrometry. We then established an oxaliplatin-resistant CRC cell model to explore the potential targets and regulatory mechanisms through which ZZF overcomes chemoresistance at the cellular level.
Results: Network pharmacology and bioinformatics analyses jointly identified 29 active compounds and 13 potential key targets of ZZF, associated with chemoresistance. Among these targets, the differential expression of CASP7 significantly affected the progression-free survival of patients with CRC. We established two oxaliplatin-resistant CRC cell lines and observed an upregulation of CASP7 expression in these resistant cells. Furthermore, ZZF increases the expression and activation of CASP7 in resistant cells, promoting apoptosis, and thereby ameliorating chemoresistance. Additionally, β-catenin knockdown led to an upregulation of CASP7 expression, whereas activation of the Wnt/β-catenin signaling pathway reduced CASP7 protein levels. ZZF decreases the activity of the Wnt/β-catenin signaling pathway by decreasing β-catenin transcription and nuclear localization.
Conclusion: ZZF has potential clinical value in the treatment of chemoresistance in CRC by inhibiting the transcription and nuclear localization of β-catenin, thereby increasing the expression of CASP7 and enhancing the apoptotic response in chemoresistant CRC cells.
期刊介绍:
Frontiers in Medicine publishes rigorously peer-reviewed research linking basic research to clinical practice and patient care, as well as translating scientific advances into new therapies and diagnostic tools. Led by an outstanding Editorial Board of international experts, this multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
In addition to papers that provide a link between basic research and clinical practice, a particular emphasis is given to studies that are directly relevant to patient care. In this spirit, the journal publishes the latest research results and medical knowledge that facilitate the translation of scientific advances into new therapies or diagnostic tools. The full listing of the Specialty Sections represented by Frontiers in Medicine is as listed below. As well as the established medical disciplines, Frontiers in Medicine is launching new sections that together will facilitate
- the use of patient-reported outcomes under real world conditions
- the exploitation of big data and the use of novel information and communication tools in the assessment of new medicines
- the scientific bases for guidelines and decisions from regulatory authorities
- access to medicinal products and medical devices worldwide
- addressing the grand health challenges around the world