Nalbuphine Suppresses Leukemia Stem Cells and Acts Synergistically with Chemotherapy Drugs via Inhibiting Ras/Raf/Mek/Erk Pathway

Retrospective clinical studies have shown that opioids could potentially affect the risk of cancer recurrence and metastasis. Better understanding of the effects of opioids on cancer will help to select the optimal anesthetic regimens to achieve better outcomes in cancer patients.Increasing evidence has shown the direct effects of opioids on bulk cancer cells and cancer stem cells. Opioid such as nalbuphine is approved to control cancer-associated pain but little is known on their possible cancer effects.To assess the biological effects of nalbuphine on acute myeloid leukemia (AML) differentiated and stem/progenitor CD34+ cells.AML CD34+ cells were isolated with colony formation, growth and apoptosis assays performed. Biochemical and immunoblotting analyses were conducted in AML cells exposed to nalbuphine.Nalbuphine at clinically relevant concentrations was active against a panel of AML cell lines with varying IC50. Importantly, nalbuphine augmented the efficacy of cytarabine and daunorubicin in decreasing AML cell viability/ growth. Besides bulk AML cells, we noted that nalbuphine was effective and selective in decreasing viability and colony formation of AML CD34+ cells while sparing normal hematopoietic CD34+ cells. The action of nalbuphine on AML cells is not associated with opioid receptors but via inhibiting Ras/Raf/MEK/ERK signaling pathway. Overexpression of constitutively active Ras partially but significantly reversed the inhibitory effects of nalbuphine on AML cells.Our findings reveal the selective anti-AML activity of nalbuphine and its ability in inhibiting Ras signaling. Our work suggests that nalbuphine may be beneficial for leukemia patients.