Morphine activates blast-phase chronic myeloid leukemia cells and alleviates the effects of tyrosine kinase inhibitors.

Morphine is an opioid analgesic drug routinely used in the postoperative period for pain management in cancer patients. In this work, we analyzed the effects of morphine on leukemia cells at all stages of development and addressed its underlying mechanism. We showed that clinically relevant concentrations of morphine promoted growth without affecting survival in blast phase-chronic myeloid leukemia (BP-CML) K562 and LAMA84 cells. In addition, morphine alleviated the anti-proliferative and pro-apoptotic effects of BCR-ABL tyrosine kinase inhibitor (TKI) in BP-CML cells. We further found that morphine increased colony formation and replating capacity of CD34 stem/progenitor derived from BP-CML patients. In addition, morphine alleviated the inhibitory effects of BCR-ABL TKIs in cell survival, colony formation and replating capacity in BP-CML CD34 + stem/progenitor cells. Mechanistic investigations demonstrated that morphine specifically activated Wnt signaling via increasing β-catenin activity and Wnt target genes transcription in K562 and CD34 + stem/progenitor cells. The effects of morphine in BP-CML were abolished by Wnt inhibitor LGK-974 or XAV939, which further confirmed that morphine protected BP-CML cells from BCR-ABL TKIs-induced toxicity via activating Wnt/β-catenin signaling. Our work demonstrated the novel role of morphine on leukemia cells. The activation of Wnt/β-catenin by morphine may provide a new guide in the clinical use of morphine, particularly in patients with Wnt-driven cancers.