Propofol enhances BCR-ABL TKIs' inhibitory effects in chronic myeloid leukemia through Akt/mTOR suppression.

BACKGROUND: The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia (CML). METHODS: We systematically examined the effect of propofol and its combination with BCR-ABL tyrosine kinase inhibitors (TKIs) in CML cell lines, patient progenitor cells and mouse xenograft model. We analyzed propofol's underlying mechanism focusing on survival pathway in CML cells. RESULTS: We show that propofol alone is active in inhibiting proliferation and inducing apoptosis in KBM-7, KU812 and K562 cells, and acts synergistically with imatinib or dasatinib, in in vitro cell culture system and in vivo xenograft model. In addition, propofol is more effective in inducing apoptosis and inhibiting colony formation in CML CD34 progenitor cells than normal bone marrow (NBM) counterparts. Combination of propofol and dasatinib significantly eliminates CML CD34 without affecting NBM CD34 cells. We further demonstrate that propofol suppresses phosphorylation of Akt, mTOR, S6 and 4EBP1 in K562. Overexpression of constitutively active Akt significantly reverses the inhibitory effects of propofol in K562, confirm that propofol acts on CML cells via inhibition of Akt/mTOR. Interestingly, the levels of p-Akt, p-mTOR and p-S6 are lower in cells treated with combination of propofol and imatinib than cells treated with propofol or imatinib alone, suggesting that propofol augments BCR-ABL TKI's inhibitory effect via suppressing Akt/mTOR pathway. CONCLUSION: Our work shows that propofol can be repurposed to for CML treatment. Our findings highlight the therapeutic value of Akt/mTOR in overcoming resistance to BCR-ABL TKI treatment in CML.

[Influence of small-dose dexmedetomidine on recovery of patients undergoing vertebral operation].

OBJECTIVE: To evaluate the influence of small-dose dexmedetomidine infusion on recovery of patients undergoing vertebral operation. METHODS: Sixty ASA I-II patients undergoing vertebral operation were randomly divided into two groups (n=30). In group I, dexmedetomidine infusion was pumped at the rate of 0.5 µg·kg(-1)·h(-1) from tracheal intubation to incision suture, and in group II, 0.9%saline was pumped instead. The mean arterial pressure, heart rate, Riker Sedation-Agitation Scale and Ramesay sedation score were recorded at the time points of autonomous respiration (T1), eye opening (T2), extubation (T3), 1 min after extubation (T4), 10 min after extubation (T5), and 30 min after extubation (T6). RESULTS: The recovery time of autonomous respiration and eye opening time in group I were significantly longer than those in group II, and the extubation time was significantly shorter in group I (P<0.05). Riker Sedation-Agitation Scale scores in group II were significantly higher than those in group I at T2 and T4, and Ramesay sedation scores in group I were significantly higher than those in group II at T1, T2 and T5 (P<0.05). The mean arterial pressure and heart rate at each time point was significantly lower in group I than in group II (P<0.05), especially at T3 and T4 (P<0.01). In both groups, the mean arterial pressure and heart rate at T3 and T4 were significantly higher than those at rest (P<0.05). CONCLUSIONS: Small-dose dexmedetomidine infusion can reduce dysphoria and lower the risks during recovery from general anesthesia following vertebral operation.