Owing to the recent emergence of drug resistance to
Bruton's tyrosine kinase inhibitors (BTK) in
chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding
hypoxia-inducible factor
prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor
molidustat showed that
molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and
VEGF, the downstream molecules of the HIF pathway, were upregulated after
molidustat treatment. Western blotting results indicated that
molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after
molidustat treatment. We further identified synergistic cytotoxicity of
molidustat in combination with
ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore,
molidustat is a potential therapeutic option for CLL.