Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia

Abstract

Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis, differentiation, S/G2/M arrest, and DNA damage. Taken together, our data demonstrate that pevonedistat and sapanisertib exhibit distinct anti-tumor effects on AML cells, i.e. cytotoxic and cytostatic effects, respectively; however, sapanisertib can attenuate pevonedistat-induced cellular responses in AML cells. Understanding mTOR and neddylation pathway interaction could provide therapeutic strategies for treatment of AML and other malignancies.

Rapamycin enhanced the antitumor effects of doxorubicin in myelogenous leukemia K562 cells by downregulating the mTOR/p70S6K pathway

“…The sensitivity of cells to doxorubicin was measured by IC 50 . The concentration of rapamycin (10, 20 and 40 nM) was added to K562 cells according to the authors' previous studies (12,14). The interaction between rapamycin and doxorubicin was assessed using the combination index (CI) (27,28).…”

“…In addition, the mTOR pathway has been found to be activated in leukemia cells, especially in cell lines expressing Bcr/Abl (8–11). Previous studies demonstrated that the mTOR pathway was activated in myeloid leukemia, including CML, and mTOR inhibitor (rapamycin, sapanisertib) could arrest cells at the G 0 /G 1 phase and increase apoptosis in leukemia cells (12–14). mTOR is a serine/threonine kinase which plays important roles in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Protein Kinase B (AKT)/mTOR pathway.…”

Drug Repurposing Approach against Novel Coronavirus Disease (COVID-19) through Virtual Screening Targeting SARS-CoV-2 Main Protease

“…There was a good correlation between MMGBSA dg Bind and binding affinity, where a more negative value suggests stronger binding affinity [31]. From the result of MM/GBSA analysis, seven drugs were found to possess a higher MM/GBSA score than the control Z45617795 (−28.33 kcal/mol) ( Sapanisertib and napabucasin are investigational anticancer drugs, which induce apoptosis of the cancer cell [32,33]. Sapanisertib demonstrated hydrogen bond interaction with ASN-142 and hydrophobic bond interactions with HIS-41, MET-49, and MET-165 ( Figure 4A).…”

Identification of a novel small nucleolar RNAs prognostic signature for patients with acute myelocytic leukemia

“…Targeted inhibition of mTOR kinase can be used as a potential strategy for the treatment of AML, and may also affect the resistance of AML to chemotherapy drugs [45]. Targeted inhibition of mTOR in AML cells can signi cantly reduce cell metabolic activity, block the cell cycle, and induce apoptosis, which may be a potential therapeutic strategy for AML [46][47][48][49]. In the process of tumor cell development and development, EMT will also cause tumor cells to lose some of the characteristics of epithelial cells to obtain some of the characteristics of interstitial cells, and also allow tumor cells to acquire stronger invasion and detachment capabilities.…”