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.

Differential role of intravenous anesthetics in colorectal cancer progression: implications for clinical application.

Anesthetics are unavoidable to colorectal cancer (CRC) patients who underwent surgical treatment. Thus, the molecular mechanisms underlying the role of the intravenous anesthetics in CRC metastasis are still unclear. In this study, the effects of intravenous anesthetics, such as propofol, etomidate and dexmedetomidine, on cell migration were determined. The migration of CRC cells was inhibited by propofol in vitro, but not in vivo. Etomidate, however, promoted the migration of CRC cells both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) mediated the promotive effect of propofol and etomidate on the migration of CRC cells through PI3K/AKT signaling pathway. Dexmedetomidine alone or in combination with propofol or etomidate had minor effect on the migration of CRC cells. These findings indicate that propofol inhibites CRC cell migration in vitro. Etomidate playes a role for prompting CRC metastasis progression by activating (PI3K)/AKT signaling and inducing EMT. It provides an important hint for the clinical application of these anesthetics.

[Effects of dexmedetomidine on propofol dosage in target-controlled infusion and hemodynamics during laparoscopic surgery under general anesthesia].

OBJECTIVE: To assess the effects of dexmedetomidine (Dex) on propofol dosage in target-controlled infusion (TCI) and hemodynamics in patients undergoing laparoscopic surgery under general anesthesia. METHODS: Sixty patients undergoing laparoscopic surgery under general anesthesia were randomly divided into control group (n=30) and the Dex group (n=30). The patients in Dex group received a loading dose of Dex (1 µg/kg, infused within 10 min) before the surgery followed by continuous infusion at the rate of 0.3 µg·kg(-1)·h(-1) till the end of the surgery, and the control patients received saline infusion in the same manner. Heart rate, blood pressure, bispectral index (BIS), and propofol dose in TCI were recorded during induction and maintenance of anesthesia. The incidence of hypotension and bradycardia were observed during and after the surgery. RESULTS: No difference was found in the incidence of hypotension and bradycardia between the control group and Dex group (P>0.05), but heart rate and blood pressure were lower in Dex group during extubation (P<0.05). The dose of propofol in TCI was significantly less in Dex group than in the control group (P<0.05). CONCLUSION: Dex can reduce hemodynamic abnormalities caused by extubation and decrease the dosage of propofol in TCI, and may serve as an ideal adjuvant drug for general anesthesia.

[Prophylactic effect of acupuncture on nausea and vomiting after laparoscopic operation].

OBJECTIVE: To explore the prophylactic effect of acupuncture Neiguan (PC 6) on nausea and vomiting after laparoscopic operation. METHODS: One hundred patients with laparoscopic gastrointestinal operation were randomly divided into an acupuncture group and a control group, 50 patients in each group. The operation was carried out with the combined infusion and inhalation anesthesia. The patients in the acupuncture group were being punctured at bilateral Neiguan (PC 6) before anesthesia and during the operation. The needles were extracted after operation, and the acupoints were covered with opaque tape. In contrast, the patients in the control group only accepted tape covering without acupuncture. After operation, all patients were given the self-controlled intravenous analgesia, and followed up at 6 h, 12 h, 24 h, 48 h for recording the incidence rate of the nausea, retching and vomiting, then scoring with VAS. RESULTS: At 6 h, 12 h, 24 h, 48 h after operation, in the acupuncture group, the incidence rates of the nausea were 12.0%, 6.0%, 6.0% and 2.0%, and the incidence rates of the retching were 0, 0, 2.0% and 2.0%, respectively; in the control group, the incidence rates of the nausea were 28.0%, 20.0%, 12.0% and 2.0%, and the incidence rates of the retching were 2.0%, 6.0%, 2.0% and 0, respectively. At 6 h, 12 h after operation, the incidence rates of the nausea and retching in the acupuncture group were lower than those of the control group (P < 0.05, P < 0.001). The vomiting was not happened in both groups. There was no difference between the two groups according to the scoring with VAS. CONCLUSION: Acupuncturing at Neiguan (PC 6) can reduce the incidence rates of the patients' nausea and retching after laparoscopic operation, especially in 24 h.