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

• Published in: BMC anesthesiology Vol. 17; no. 1; p. 132
• Main Authors: Tan, Zhimin, Peng, Aixia, Xu, Jingwen, Ouyang, Mingwen
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-09-2017; BioMed Central; BMC
• Subjects: Abl protein; AKT protein; Akt/mTOR; Animals; Apoptosis; BCR protein; Binding sites; Bone marrow; Breast cancer; Cancer; CD34 antigen; Cell culture; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cervical cancer; Chemical properties; Chronic myeloid leukemia; Dose-Response Relationship, Drug; Drug repurposing; Drug therapy; Experiments; Fusion protein; Fusion Proteins, bcr-abl - pharmacology; Fusion Proteins, bcr-abl - therapeutic use; Humans; Hypnotics and Sedatives - pharmacology; Hypnotics and Sedatives - therapeutic use; Imatinib; Imatinib mesylate; Intravenous administration; K562 Cells; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Male; Mice; Mice, Inbred NOD; Mice, SCID; Microscopy; Myeloid leukemia; Osteoprogenitor cells; Ovarian cancer; Phosphorylation; Physiological aspects; Propofol; Propofol - pharmacology; Propofol - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Random Allocation; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor Burden - drug effects; Tumor Burden - physiology; Xenograft Model Antitumor Assays - methods; Xenografts; United States > US; Drug repurposing; Propofol; Akt/mTOR; Leukemia
• ISSN: 1471-2253; 1471-2253
• DOI: 10.1186/s12871-017-0423-2

The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia (CML).
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.
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.
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.