Local Anesthetic Drug Inhibits Growth and Survival in Chronic Myeloid Leukemia Through Suppressing PI3K/Akt/mTOR

Abstract

BackgroundApart from the known anesthetic and antiarrhythmic effects, recent studies also highlight the anticancer activities of local anesthetics. In line with the findings, our work shows that ropivacaine, an amide-linked local anesthetic drug, targets chronic myeloid leukemia (CML) via inhibiting PI3K/Akt/mTOR. Materials and MethodsThe effects of ropivacaine in CML cell lines and primary stem or progenitor cells were investigated using apoptosis, proliferation and colony formation assays. The effects of ropivacaine on proliferation and survival pathways were analyzed using Western blot. ResultsWe demonstrate that ropivacaine dose and time dependently inhibits proliferation in CML cell lines via arresting cell at G2/M stage. Ropivacaine induces apoptosis in CML cells. In addition, the anti-CML activity of ropivacaine is mainly through growth arrest rather than apoptosis induction. We further demonstrate that ropivacaine induces apoptosis and inhibits colony formation in CD34 progenitor or stem cells derived from patients with blast phase-CML. Importantly, combination of ropivacaine with imatinib or dasatinib (Bcr-Abl tyrosine kinase inhibitors) is significantly more effective in targeting CML cell lines as well as blast phase-CML CD34 cells than imatinib or dasatinib alone. We further demonstrate that ropivacaine inhibits phosphorylation of essential molecules involved in PI3K/Akt/mTOR signaling pathways in CML cells. Akt overexpression significantly reverses the effects of ropivacaine, further confirming that ropivacaine acts on CML cells via inhibition of PI3K/Akt/mTOR. ConclusionsOur work provide rationales on clinical trials for the use of local anesthetics in CML by demonstrating the anti-CML effects of ropivacaine and the molecular mechanism of its action.