Abstract
Background: Cyclophosphamide is a common tumor chemotherapy drug used to treat various cancers. However, the resulting immunosuppression leads to leukopenia, which is a serious limiting factor in clinical application. Therefore, the introduction of immunomodulators as adjuvant therapy may help to reduce the hematological side effects of cyclophosphamide. Lvjiaobuxue granule has been widely used in the clinical treatment of gynecological diseases such as anemia and irregular menstruation. Recently, it has been found to increase the function of white blood cells, but its mechanism of action is still unclear. We aimed to reveal the mechanisms of Lvjiaobuxue granule against acute leukopenia by an integrated strategy combining metabolomics with network pharmacology. Methods: Subcutaneously inoculated 4T1 breast cancer cells to prepare tumor-bearing mice, intraperitoneal injection of cyclophosphamide to establish a 4T1 tumor-bearing mice leukopenia animal model, using pharmacodynamic indicators, metabolomics, network pharmacology and molecular biology and other technical methods. To comprehensively and systematically elucidate the effect and mechanism of Lvjiaobuxue granule in improving cyclophosphamide-induced leukopenia in 4T1 tumor-bearing mice. Results: Lvjiaobuxue granule can improve the blood routine parameters and organ index levels of the leukopenia model of 4T1 tumor-bearing mice. Metabolomics studies revealed that 15 endogenous metabolites in the spleen of mice were considered as potential biomarkers of Lvjiaobuxue granule for their protective effect. Metabonomics and network pharmacology integrated analysis indicated that Lvjiaobuxue granule exerted the leukocyte elevation activity by inhibiting the branched-chain amino acids (BCAAs) degradation pathway and increasing the levels of valine, leucine and isoleucine. The results of molecular biology also showed that Lvjiaobuxue granule can significantly regulate the key enzymes in the catabolism of BCAAs, which further illustrates the importance of BCAAs in improving leukopenia. Conclusion: Lvjiaobuxue granule exerts obvious pharmacological effects on the leukopenia model of 4T1 tumor-bearing mice induced by cyclophosphamide, which could be mediated by regulating the branched-chain amino acid degradation pathway and the levels of valine, leucine and isoleucine.
Highlights
Cyclophosphamide is the most common cancer chemotherapy agent and used in anticancer for various types of cancer, especially breast cancer (Futamura et al, 2017; Hung et al, 2017)
The branched-chain keto acid dehydrogenase E1 (BCKDHA) and Acyl-CoA Dehydrogenase Short Chain (ACADS) enzyme levels in the model group were significantly increased in the catabolism pathway of BCAAs
The major new findings were that Lvjiaobuxue granule could improve cyclophosphamide-induced leukopenia in 4T1 tumor-bearing mice, accelerate the recovery of spleen, thymus and liver indices, accelerate the recovery of white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), Mo, and red blood cell count (RBC) contents, and the recovery of spleen metabolite levels in the mice spleen caused by leukopenia
Summary
Cyclophosphamide is the most common cancer chemotherapy agent and used in anticancer for various types of cancer, especially breast cancer (Futamura et al, 2017; Hung et al, 2017). Immunosuppression induced by cyclophosphamide causes the occurrence of leukopenia, which is a seriously limiting factor in a clinical application (Deng et al, 2018; Sun et al, 2018). Prescriptions are composed of a combination of multiple drugs, which are considered to be a promising treatment strategy to improve the anti-tumor effect and reduce the side effects of chemotherapy drugs (Mellor et al, 2010). The resulting immunosuppression leads to leukopenia, which is a serious limiting factor in clinical application. Lvjiaobuxue granule has been widely used in the clinical treatment of gynecological diseases such as anemia and irregular menstruation. We aimed to reveal the mechanisms of Lvjiaobuxue granule against acute leukopenia by an integrated strategy combining metabolomics with network pharmacology
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