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

Li, Jie; Liu, Wenjing; Huang, Hao; Wang, Qiuyi; Xue, Liang

doi:10.3892/ol.2019.10589

Cited by 12 publications

(16 citation statements)

References 44 publications

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“…The cell viability between RAPA ω-liposomes and GC-DOX/RAPA ω- liposomes was not significantly different (0.1 ~ 2 nM of drug concentration), however, the combination of RAPA and DOX generally exhibited greater inhibition of cell proliferation than either drug alone. The CI value was significantly less than 1 (0.175), which is an indication of the high synergy between RAPA and DOX (Figure S3) [38]. Although the therapeutic effect of GC-DOX/RAPA ω- liposomes was extremely high, the additional remote loading method for DOX into liposomes could have led to a higher drug loading, thus improving the therapeutic efficacy [39].…”

Section: Resultsmentioning

confidence: 99%

Glycol Chitosan-Docosahexaenoic Acid Liposomes for Drug Delivery: Synergistic Effect of Doxorubicin-Rapamycin in Drug-Resistant Breast Cancer

2019

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Marine ecosystems are the most prevalent ecosystems on the planet, providing a diversity of living organisms and resources. The development of nanotechnology may provide solutions for utilizing these thousands of potential compounds as marine pharmaceuticals. Here, we designed a liposomal glycol chitosan formulation to load both doxorubicin (DOX) and rapamycin (RAPA), and then evaluated its therapeutic potential in a prepared drug-resistant cell model. We explored the stability of the drug delivery system by changing the physiological conditions and characterized its physicochemical properties. The electrostatic complexation between DOX-glycol chitosan and docosahexaenoic acid RAPA-liposomes (GC-DOX/RAPA ω-liposomes) was precisely regulated, resulting in particle size of 131.3 nm and zeta potential of −14.5 mV. The well-characterized structure of GC-DOX/RAPA ω-liposomes led to high loading efficiencies of 4.1% for DOX and 6.2% for RAPA. Also, GC-DOX/RAPA ω-liposomes exhibited high colloidal stability under physiological conditions and synergistic anti-cancer effects on DOX-resistant MDA-MB-231 cells, while showing pH-sensitive drug release behavior. Our results provided a viable example of marine pharmaceuticals with therapeutic potential for treating drug-resistant tumors using an efficient and safe drug delivery system.

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Section: Resultsmentioning

confidence: 99%

Glycol Chitosan-Docosahexaenoic Acid Liposomes for Drug Delivery: Synergistic Effect of Doxorubicin-Rapamycin in Drug-Resistant Breast Cancer

2019

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“…K562 and K562/A cells were cultured at 37°C and treated with various concentrations of BEZ235 (25, 50, 100, 200, 400, 800 and 1,600 nM) for 24 h or with 200 nM BEZ235 for 0.5, 1, 2 and 3 days. Meanwile, the cells were treated with various concentrations of Doxo (31.25, 62.5, 125, 250, 500, 1,000 and 2,000 nM) according to our previously published paper ( 9 ). After the cells were incubated with 10 µl CCK-8 reagent at 37°C for 4 h, the cytotoxic effect of BEZ235 on K562/A cells was measured on a spectrophotometer microplate reader (BioTek Instruments, Inc.) at a wavelength of 450 nm.…”

Section: Methodsmentioning

confidence: 99%

“…It was previously demonstrated that the mTOR pathway is upregulated in CML, and rapamycin can arrest cells at the G 0 /G 1 phase and promote apoptosis of K562 cells ( 8 ). In addition, rapamycin enhances the antitumor effects of Doxo by downregulating the mTOR/ribosomal protein S6 kinase (p70S6K) pathway ( 9 ). Therefore, targeting the mTOR pathway may increase cell sensitivity to Doxo and serve as an effective therapeutic approach to leukemia.…”

Section: Introductionmentioning

confidence: 99%

“…BEZ235 can also induce apoptosis and enhance autophagic activity, as well as inhibit the proliferation of leukemia cells ( 18 , 19 ). Furthermore, BEZ235 was identified to enhance the accumulation of Doxo in drug-resistant ovarian and pancreatic cancer cells ( 9 ). However, the effect of BEZ235 on Doxo-resistant K562 cells (K562/A) has not been extensively reported.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2021

Mol Med Rep

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Acute myelogenous leukemia (AML) is frequently accompanied by a poor prognosis. The majority of patients with AML will experience recurrence due to multiple drug resistance. Our previous study reported that targeting the mTOR pathway may increase cell sensitivity to doxorubicin (Doxo) and provide an improved therapeutic approach to leukemia. However, the effect and mechanism of action of NVP-BEZ235 (BEZ235), a dual inhibitor of PI3K/mTOR, on Doxo-resistant K562 cells (K562/A) is yet to be elucidated. Therefore, the aim of the present study was to investigate the effects of BEZ235 on K562/A cell proliferation. K562/A cells was investigated using CCK-8, flow cytometry and western blotting, following BEZ235 treatment. It was observed that BEZ235 significantly decreased the viability of K562/A cells. In addition, BEZ235 arrested K562/A cells at the G 0 /G 1 phase, and reduced the protein expression levels of CDK4, CDK6 and cyclin D1. Apoptotic cells were more frequently detected in K562/A cells treated with BEZ235 compared with the control group (12.97±0.91% vs. 7.37±0.42%, respectively; P<0.05). Cells treated with BEZ235 exhibited downregulation of Bcl-2 and upregulation of Bax. Furthermore, BEZ235 treatment markedly decreased the activation of the PI3K/AKT/mTOR pathway and its downstream effectors. Thus, these results demonstrated that BEZ235 inhibited cell viability, induced G 0 /G 1 arrest and increased apoptosis in K562/A cells, suggesting that BEZ235 may reverse Doxo resistance in leukemia cells. Therefore, targeting the PI3K/mTOR pathway may be of value as a novel therapeutic approach to leukemia.

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“…The mTOR/p70S6K signaling pathway promotes cell proliferation in diverse cell types, including gastric cancer cells, myelogenous leukemia K562 cells, and VSMCs. 18 19 20 In particular, phosphorylations of mTOR at Ser2448 and p70S6K at Thr389 are essential for their activation and consequent cell proliferation. 21 Furthermore, AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleotide was reported to inhibit the mTOR/p70S6K signaling pathway in human umbilical vein endothelial cells (HUVECs) and VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Activation of Adenosine Monophosphate-activated Protein Kinase by Telmisartan Decreases Basal and Platelet-derived Growth Factor-stimulated Vascular Smooth Muscle Cell Proliferation via Inhibiting the Mammalian Target of Rapamycin/p70 S6 Kinase Signaling Axis

2020

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Background: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is widely used to treat hypertension by blocking the renin-angiotensin-aldosterone system. Although abnormal proliferation of vascular smooth muscle cells (VSMCs) is a well-established contributor to the development of various vascular diseases, such as atherosclerosis, the effect of telmisartan on VSMC proliferation and its mechanism of action have not been fully revealed. Herein, we investigated the molecular mechanism whereby telmisartan inhibits rat VSMC proliferation. Methods: We measured VSMC proliferation by MTT assay, and performed inhibitor studies and western blot analyses using basal and platelet-derived growth factor (PDGF)-stimulated rat VSMCs. To elucidate the role of AMP-activated protein kinase (AMPK), we introduced dominant-negative (dn)-AMPKα1 gene into VSMCs. Results: Telmisartan decreased VSMC proliferation, which was accompanied by decreased phosphorylations of mammalian target of rapamycin (mTOR) at Ser2448 (p-mTOR-Ser 2448) and p70 S6 kinase (p70S6K) at Thr389 (p-p70S6K-Thr 389) in dose-and time-dependent manners. Telmisartan dose-and time-dependently increased phosphorylation of AMPK at Thr172 (p-AMPK-Thr 172). Co-treatment with compound C, a specific AMPK inhibitor, or ectopic expression of the dn-AMPKα1 gene, significantly reversed telmisartan-inhibited VSMC proliferation, p-mTOR-Ser 2448 and p-p70S6K-Thr 389 levels. Among the ARBs tested (including losartan and fimasartan), only telmisartan increased p-AMPK-Thr 172 and decreased p-mTOR-Ser 2448 , p-p70S6K-Thr 389 , and VSMC proliferation. Furthermore, GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist, did not affect any of the telmisartan-induced changes. Finally, telmisartan also exhibited inhibitory effects on VSMC proliferation by increasing p-AMPK-Thr 172 and decreasing p-mTOR-Ser 2448 and p-p70S6K-Thr 389 in a PDGF-induced in vitro atherosclerosis model. Conclusion: These results demonstrated that telmisartan-activated AMPK inhibited basal and PDGF-stimulated VSMC proliferation, at least in part, by downregulating the mTOR/p70S6K signaling axis in a PPARγ-independent manner. These observations suggest that telmisartan could be used to treat arterial narrowing diseases such as atherosclerosis and restenosis.

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

Cited by 12 publications

References 44 publications

Glycol Chitosan-Docosahexaenoic Acid Liposomes for Drug Delivery: Synergistic Effect of Doxorubicin-Rapamycin in Drug-Resistant Breast Cancer

Glycol Chitosan-Docosahexaenoic Acid Liposomes for Drug Delivery: Synergistic Effect of Doxorubicin-Rapamycin in Drug-Resistant Breast Cancer

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

Activation of Adenosine Monophosphate-activated Protein Kinase by Telmisartan Decreases Basal and Platelet-derived Growth Factor-stimulated Vascular Smooth Muscle Cell Proliferation via Inhibiting the Mammalian Target of Rapamycin/p70 S6 Kinase Signaling Axis

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