Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells.

Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia and BCR-ABL1 inhibitor monotherapy fails to eliminate them, thereby necessitating alternate therapeutic strategies. Peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone downregulates signal transducer and activator of transcription 5 (STAT5) and in combination with imatinib induces complete molecular response in imatinib-refractory patients by eroding leukemia stem cells. Thiazolidinediones like pioglitazone however, are associated with severe side effects. To identify alternate therapeutic strategies for chronic myeloid leukemia we screened FDA-approved drugs in K562 cells and identified the leprosy drug clofazimine as an inhibitor of viability. Here we show that clofazimine induces apoptosis in chronic myeloid leukemia patient-derived blood mononuclear cells, with particularly robust effect in imatinib-resistant cells. Clofazimine also induced apoptosis in CD34+38- progenitors and quiescent CD34+ cells from chronic myeloid leukemia patients but not healthy donor-derived hematopoietic progenitors. Mechanistic evaluation revealed that clofazimine via physical interaction with PPARγ induced nuclear factor kB-p65 proteasomal degradation, which led to sequential MYB and peroxiredoxin 1 downregulation and concomitant induction of reactive oxygen species-mediated apoptosis. Clofazimine also suppressed STAT5 expression and consequently downregulated stem cell maintenance factors hypoxia-inducible factor -1α and -2α and Cbp/P300 Interacting Transactivator with Glu/Asp rich Carboxy-Terminal Domain 2. Combining imatinib with clofazimine caused a far superior synergy than pioglitazone where clofazimine reduced imatinib's IC50 by >4 logs and remarkably eroded quiescent CD34+ cells. In a K562 xenograft study clofazimine and imatinib co-treatment showed more robust efficacy than individual treatments. We propose clinical evaluation of clofazimine in imatinib-refractory chronic myeloid leukemia.