Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Li, Jie; Wang, Xiaozi; Ma, Chuanbao; Xu, Shasha; Xu, Mengyao; Yang, Jie; Wang, Rui-Cang; Xue, Liang

doi:10.3892/mmr.2021.11940

Cited by 8 publications

(7 citation statements)

References 14 publications

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“…Its activation promotes cell cycle progression by downregulation of cyclin D1, maintains cell survival through inactivation of Bad meanwhile increase of the expression of Bcl-2 protein, and promotes cell growth by phosphorylation of the downstream mTOR. Treated with FD268, our studies documented the reduction of PI3K/Akt process and downregulation in the level of phosphorylated mTOR as well as its downstream targets p70S6K at Thr389 and 4EBP1 in both HL-60 and MOLM-16 cells, which is in agreement with those well-known PI3K inhibitors in treatment of AML [ 26 , 46 , 47 ]. Although it is hard to reveal the cell-line-dependent regulation of cell cycle arrest and completely map the mechanisms of actions in AML, our studies, together with KEGG pathway analysis, demonstrated the capacity of FD268 in suppressing cell proliferation and inducing apoptosis on AML through inhibition of PI3K/Akt/mTOR signaling pathway ( Fig 9 ).…”

Section: Discussionsupporting

confidence: 88%

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia

Chen

Yang

et al. 2022

PLoS ONE

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Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.

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Section: Discussionsupporting

confidence: 88%

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia

Chen

Yang

et al. 2022

PLoS ONE

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“…BEZ235 treatment decreased proliferation and confluency in TdTomato-4T1 cells, with treated cells showing reduced rates of proliferation over 5 days compared to untreated cells (Fig 3 .6A, B). BEZ235 therefore had an effect on TdTomato-4T1 proliferation, consistent with literature and the cytostatic mechanism of action of BEZ235 214,215 . Fluctuations in confluency measurements were seen in the 1.2µM treated conditions.…”

Section: Discussionsupporting

confidence: 88%

'I get by with a little help from my friends': The role of stromal cells in the breast cancer chemoresistance mechanism

Thompson¹

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Breast cancer is the most common cancer that affects women worldwide, and in New Zealand accounts for 1/3 of new cancer cases. The tumour microenvironment (TME) has an important role in how breast cancer cells respond to chemotherapeutic stress. Mesenchymal stromal cells (MStCs), a component of the TME, have been shown to function in the development of breast cancer cell chemoresistance, promoting survival and more aggressive cancer cell phenotypes. The effect of co-culture on the 4T1 murine breast cancer cell response to chemotherapy has been explored with DNA-damaging therapies but was yet to be explored against other chemotherapeutic mechanisms. Fluorescent-4T1 cells were co-cultured with compact bone-derived MStCs and treated with chemotherapies of differing modalities. Flow cytometry, microscopy and gene expression assays were used to assess the effect of co-culture on the 4T1 response to treatment with clinically relevant chemotherapy drugs. Fluorescent-4T1s had altered morphology, disrupted cell cycles, and decreased viability in response to drug treatment. MStCs had low positive expression of classical stromal markers and had reduced effects of chemotherapy compared to 4T1s. Co-culture with MStCs decreased the effect of drug on 4T1 viability, morphology and cell cycle progression. Increased contact between 4T1s and MStCs resulted in enhanced survival of 4T1 cells under chemotherapeutic stress. These results indicated that drug efficacy is decreased when cancer cells are in co-culture with supporting cells of the TME, independent of the modality of chemotherapeutic stress. This emphasises the importance of the TME to the cancer cell stress response and begins to delve into potential mechanisms for this enhanced interaction. Future research should investigate candidates for inhibiting this interaction between stromal and cancer cells.

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“…The mTOR kinase is responsible for phosphorylating downstream proteins, such as AKT, which are recognized as significant in promoting cancer growth 29,30 . Small‐molecule inhibitors that have been developed and extensively validated for their tumor‐suppressing effects target the PI3K/mTOR pathway 13,31,32 . The activation of the PI3K/AKT/mTOR pathway has been reported in AML cells, 13,33 and targeting this signaling pathway has demonstrated beneficial therapeutic effects on AML both in vitro and in vivo 13,34 .…”

Section: Discussionmentioning

confidence: 99%

SIRT2 inhibitor SirReal2 enhances anti‐tumor effects of PI3K/mTOR inhibitor VS‐5584 on acute myeloid leukemia cells

Luo,

Zhao,

Zhu

et al. 2023

Cancer Medicine

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BackgroundAcute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.MethodsThe up‐regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.ResultsThrough bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small‐molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS‐5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS‐5584 induced apoptosis and cycle arrest of AML cells in a dose‐ and time‐dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS‐5584 treatment, with 287 proteins being down‐regulated and 71 proteins being up‐regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS‐5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS‐5584 caused a significant reduction in the half‐maximal inhibitory concentration (IC50) of VS‐5584 on AML cells. In vivo, experiments suggested that VS‐5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.ConclusionsTaken together, the PI3K/mTOR inhibitor VS‐5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

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Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Cited by 8 publications

References 14 publications

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia

'I get by with a little help from my friends': The role of stromal cells in the breast cancer chemoresistance mechanism

SIRT2 inhibitor SirReal2 enhances anti‐tumor effects of PI3K/mTOR inhibitor VS‐5584 on acute myeloid leukemia cells

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