Propofol enhances BCR-ABL TKIs\u2019 inhibitory effects in chronic myeloid leukemia through Akt/mTOR suppression

Zhimin Tan,Jingwen Xu,Mingwen Ouyang,Aixia Peng

doi:10.1186/s12871-017-0423-2

Abstract

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

Highlights

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 show that propofol is effective in targeting multiple aspects of CML cells and acts synergistically with BCR-ABL Tyrosine kinase inhibitor (TKI) in vitro and in vivo
Propofol is active against CML cells and significantly augments BCR-ABL TKI’s effects We examine the effect of propofol by performing cell growth and survival assays in CML cells exposed to various concentrations of propofol

Summary

Introduction

The anti-cancer activities of intravenous anesthetic drug propofol have been demonstrated in various types of cancers but not in chronic myeloid leukemia (CML). Patients achieving remission with BCR-ABL TKIs continue to have molecular evidence of persistent disease and Propofol is a general sedative reagent and commonly used for induction and maintenance of general anesthesia [9]. It has advantages over other anesthetic drugs by protecting neuron and endothelial cells from oxidative stress and hypoxia injury [10, 11]. The mechanism of action of propofol in cancer is not completely understood and seems to be different in various tumor types It kills lung cancer cells via inducing endoplasmic reticulum stress [16] whereas promotes cervical cancer cell apoptosis via inhibiting mTOR pathway [18]

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Conclusion