Fentanyl inhibits acute myeloid leukemia differentiated cells and committed progenitors via opioid receptor-independent suppression of Ras and STAT5 pathways.

Fentanyl is a common sedative/analgesic used for intrathecal chemotherapy injection in children with acute leukemia. Given the contradictory findings that fentanyl has both inhibitory and stimulatory activities in cancer cells, we investigated the biological effects of fentanyl alone and its combination with standard of care in acute myeloid leukemia (AML) cells at all stages of development. We showed that fentanyl at clinically relevant concentration inhibited growth and colony formation of AML differentiated cells and committed progenitors without affecting their survival. Compared to AML cells without FLT3 mutation, cells harboring FLT3-ITD mutation are likely to be more sensitive to fentanyl. However, fentanyl did not affect the most primitive AML stem cells. Fentanyl significantly augmented the efficacy of cytarabine but not midostaurin in AML differentiated cells and committed progenitors. We further demonstrated that fentanyl inhibited AML cells via suppressing Ras/Raf/MEK/ERK and STAT5 pathway, and this was not dependent on opioid receptor system. Our findings demonstrate the anti-leukemia activity of fentanyl and synergistic effects between fentanyl and cytarabine in AML, via opioid receptor-independent suppression of Ras and STAT5 pathways. Our work is the first to suggest the beneficial effects of fentanyl in children with leukemia.