Cordycepin deteriorates 5' fluorouracil-induced anaemia by AMPK activation

Cordycepin (COR) is a compound extracted from Cordyceps sinensis. We found that COR exacerbates the acute anaemia induced by 5' fluorouracil (5-FU). Healthy mice were intraperitoneally injected with COR at doses of 2, 4, or 8 mg/kg for 10 consecutive days, which produced a slight decrease in the red cell distribution width in the peripheral blood and a reduction in the erythroblast levels in the spleen. Furthermore, COR (8 mg/kg) treatment delayed reticulocyte recovery when 5-FU was used to induce anaemia. A single 5-FU dose decreased the levels of reticulocytes and erythroblasts compared with those in the control mice; this decrease was more pronounced when COR was also administered. The percentage of reticulocytes was lower in the bone marrow of COR-treated mice than in the 5-FU group. COR treatment inhibited erythroid differentiation, characterised by a decrease in the proportion of erythroblasts and low mRNA levels of Hba, Hbb, Uros, Gata-1, and Epb42, compared with the control mice; these effects were reversed by treatment the AMPK inhibitor, compound C. COR treatment also reduced the mitochondrial membrane potential. Mitochondrial matrix genes, such as those involved in haeme synthesis (Alas-2), metabolic enzymes (Pck2 and Mthfd2), the respiratory chain (Ndufs7), and autophagy (Atg4a and Atg4d) were downregulated in the COR-treated erythroid precursors. Compound C reversed the COR-induced decrease in the mitochondrial membrane potential as well as Alas-2, Pck2, Atg4a, and Atg4d mRNA levels. COR treatment substantially delayed reticulocyte recovery in the peripheral blood and reduced the number of erythroblasts in the spleen following 5-FU-induced anaemia. The mechanism of action of COR involves inhibiting erythroid differentiation via activating AMPK.