Asperuloside alleviates cyclophosphamide-induced myelosuppression by promoting AMPK/mTOR pathway-mediated autophagy

Abstract

Cyclophosphamide (CTX) is a common anticancer chemotherapy drug, and myelosuppression is the most common serious side effect. Asperuloside (ASP), the active component of Hedyotis diffusa Willd., may have the effect of ameliorating chemotherapy-induced myelosuppression. This study aimed to explore the effect and possible mechanism of ASP on CTX-induced myelosuppression. Male SPF C57BL/6 mice were randomly divided into five groups: control group, CTX (25 mg/kg) group, CTX + granulocyte-macrophage-colony stimulating factor (GM-CSF) (5 μg/kg) group, CTX + high-dose ASP (50 mg/kg) group and CTX + low-dose ASP (25 mg/kg) group, with six mice in each group. The body weight of mice was monitored every other day, the hematopoietic progenitor cell colony number was measured by colony forming unit, and the relevant blood indicators were detected. Femoral bone marrow was observed by hematoxylin-eosin, C-kit expression was detected by immunohistochemistry, and autophagy and adenine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway protein expressions were detected by immunohistochemistry and western blotting (WB). Then the AMPK inhibitor dorsomorphin was used to interfere with AMPK/mTOR pathway. Results showed that ASP significantly increased the body weight of CTX-induced mice, increased the number of hematopoietic progenitor cells, the expression of white blood cells, red blood cells, platelets, GM-CSF, thrombopoietin and erythropoietin in blood, and the expression of C-kit in bone marrow. In addition, ASP further promoted the expression of Beclin1 and LC-3II/I induced by CTX, and regulated the protein expressions in the AMPK/mTOR pathway. The use of dorsomorphin inhibited the alleviation effect of ASP on CTX-induced myelosuppression and the promotion effect of ASP on autophagy. In conclusion, ASP alleviated CTX-induced myelosuppression by promoting AMPK/mTOR pathway-mediated autophagy.

Keywords: AMPK/mTOR pathway; Asperuloside; autophagy; cyclophosphamide; myelosuppression.