Alisertib induces apoptosis and autophagy through targeting the AKT/mTOR/AMPK/p38 pathway in leukemic cells

Abstract

Alisertib, a potent and selective Aurora kinase A inhibitor, has been demonstrated to exert potent anti-cancer effects in pre-clinical and clinical studies. However, mechanisms of action of alisertib, including the molecular pathways involved in alisertib-induced apoptosis and autophagy of leukemic cells, have remained elusive. The aim of the present study was to investigate the effects of alisertib on cell growth, apoptosis and autophagy and to delineate the possible molecular mechanisms in leukemic cells. Acid phosphatase, MTT and Annexin V/propidium iodide staining assays as well as immunostaining for light chain 3B showed that treatment of the REH leukemia cell line with alisertib exerted potent growth inhibitory effects, and induced apoptosis and autophagy in a dose‑dependent manner. Western blot analysis indicated that these effects may be attributed to the suppression of the activity of the Akt/mammalian target of rapamycin/5'-AMP-dependent kinase/p38 mitogen-activated protein kinase signaling pathways in REH cells. The present study confirmed that alisertib may represent a promising autophagy-inducing drug for the treatment of leukemia and shed light on its molecular mechanism of action.

Synergistic Cytotoxicity of Melatonin and New-generation Anticancer Drugs Against Leukemia Lymphocytes but not Normal Lymphocytes

“…It has been demonstrated that aurora B kinase, which exists in a complex with survivin and mTOR, synergistically regulates survival and proliferation of leukemia and lymphoma cells via crass-talk with AKT, mTOR and NOTCH signaling pathways (73,74). Moreover, several studies have reported that aurora kinase inhibitors induce cell-cycle arrest and apoptosis of cancer cells through p38 MAPK and AKT/mTOR signaling (75,76). Therefore, the synergistic cytotoxicity of the combination of barasertib plus melatonin towards leukemia lymphocytes could be explained by amplification of the effects of both substances on both molecular targets -aurora B kinase and mTOR.…”

“…In conclusion, there are many data regarding sensitization of cancer cells to conventional anticancer drugs (such as doxorubicin, bleomycin, cisplatin) by melatonin (34,46,47,(53)(54)(55)(56)(57), but only a limited number of studies have described the effect of melatonin on the cytotoxicity of new-generation anticancer drugs (recently approved for clinical use or still in clinical trials) (75)(76)(77). There are no data about the effect of melatonin on the efficiency of new-generation anticancer drugs described in the present study: AZD7762 (a selective inhibitor of checkpoint kinases), ABT-737 (a selective inhibitor of BCL2 proteins), barasertib (a selective inhibitor of aurora B kinase), everolimus (mTOR inhibitor), lonafarnib (a farnesyltrasferase inhibitor), MG132, MLN-2238 and bortezomib (proteasome inhibitors), and palbociclib (a selective inhibitor of cyclindependent kinases).…”

Ginsenoside Rg3 attenuates sepsis-induced injury and mitochondrial dysfunction in liver via AMPK-mediated autophagy flux

“…The regulation of autophagy is complicated which involves multiple signal pathways, including mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB, and mitogen-activated protein kinase (MAPK)-mediated signaling pathway etc. [ 12 – 14 ]. The renewal of mitochondria depends on autophagy, yet the relationship amongst autophagy, ROS signal, and mitochondrial dysfunction is still not clear; but when autophagy is blocked, the aggregation of toxic protein and mitochondrial dysfunction will further aggravate oxidative stress [ 4 , 10 , 15 ].…”

Activation of Adenosine 2A receptor inhibits neutrophil apoptosis in an autophagy-dependent manner in mice with systemic inflammatory response syndrome

“…Autophagy is generally believed to be a “double-edged sword” that controls the fate of cells because it not only helps cell survive during nutrient deprivations or other stresses, but also jeopardizes cells and induces cell death. In some cells, such as breast cancer cells 8 , leukemic cells 9 and neurons 10 , autophagy and apoptosis cooperate to regulate cell survival and death. However, whether apoptosis and autophagy of neutrophils in SIRS are positivlye or negatively correlated, and whether some molecules can regulate the two essential processes synergistically are not clear.…”