Abstract
Jian-pi-bu-xue-formula (JPBXF), a TCM formula composed of twelve Chinese medicinal herbs, has been used in clinic to ease patients’ state of weakness and fatigue especially after receiving anti-tumor chemotherapy in China. The lack of the phytochemical characterization, detail therapeutic evaluation and mechanism of JPBXF remains the main limitation for its spreading. In this study, we systematically evaluated the effectiveness and underline mechanism of JPBXF on cyclophosphamide (CTX)-induced myelosuppression and identified the main constituents of JPBXF aqueous extract. JPBXF treatments reversed CTX-induced myelosuppression through increasing the number of haematopoietic stem cells (HSCs) and expression of C-kit in bone marrow cells. Simultaneously, JPBXF treatments alleviated CTX-induced blood cells reduction by increasing numbers of RBCs and WBCs and levels of GM-CSF, TPO and EPO in plasma. JPBXF treatments reduced CTX-induced immunosuppression by increasing expressions of CD3, CD4, and CD8a in PBMCs, and recovering structure damages of thymus and spleen. Moreover, JPBXF notably increased the expression of NRF2 compared with CTX group, and subsequently up-regulated HO1 and NQO1 both in mRNA and protein levels. In addition, eighteen compounds were recognized from JPBXF aqueous extract and the potential targets of the identified compounds were predicted. Overall, JPBXF can greatly reverse CTX-induced myelosuppression in C57BL/6 mice, especially in improving the blood and immune function through activating NRF2/HO1/NQO1 signaling pathway, which provides a reliable reference for JPBXF application in clinical. By recognizing eighteen compounds in JPBXF aqueous extract and predicting the underline mechanisms of the identified compounds, our study would provide theoretical guidance for further research of JPBXF.
Highlights
Cancer, an aggressive malignancy, approximately causes 4,285,033 new cases and 2,865,147 cancer-related deaths annually in China (Bray et al, 2018)
The up-regulation of HO1 and NQO1 could resist to CTX-induced bone marrow suppression, oxidative stress, Abbreviations: BATMAN-Traditional Chinese medicine (TCM), Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine; CTX, cyclophosphamide; DAVID, Database for Annotation, Visualization and Integrated Discovery; ELISA, enzyme-linked immunosorbent assay; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; JPBXF, Jian-pi-bu-xue-formula; PBMC, peripheral blood mononuclear cell; PPI, protein-protein interaction; TCM, traditional Chinese medicine; TPO, thrombopoietin
Our results showed that the expressions of NRF2 were significantly decreased by CTX both in thymus and spleen compared with control group, notably increased by GM-CSF and JPBXF treatments compared with CTX group, suggesting that JPBXF could mitigate CTX-induced myelosuppression through activating of NRF2 (Figure 7A)
Summary
An aggressive malignancy, approximately causes 4,285,033 new cases and 2,865,147 cancer-related deaths annually in China (Bray et al, 2018). The conventional therapies for cancer treatment include chemotherapy, radiotherapy and surgery. Among these treatments, chemotherapy acts as a practical method and was widely used to kill cancer cells by impeding their growth and reproduction (Potti et al, 2011). Cyclophosphamide (CTX), a common anti-cancer chemotherapeutic agent, is often used alone or in combination with platinum and paclitaxel as standard first-line therapy (Handolias et al, 2016). Myelosuppression, the most common side effect of CTX characterized by decrease of stem and progenitor cells in bone marrow, often arises complications such as neutropenia, anemia and thrombocytopenia (Carey, 2003; Neboh and Ufelle, 2015). The up-regulation of HO1 and NQO1 could resist to CTX-induced bone marrow suppression, oxidative stress, Abbreviations: BATMAN-TCM, Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine; CTX, cyclophosphamide; DAVID, Database for Annotation, Visualization and Integrated Discovery; ELISA, enzyme-linked immunosorbent assay; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; JPBXF, Jian-pi-bu-xue-formula; PBMC, peripheral blood mononuclear cell; PPI, protein-protein interaction; TCM, traditional Chinese medicine; TPO, thrombopoietin
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