Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Liu, Chang; Mu, Xiuli; Wang, Xuan; Zhang, Chan; Zhang, Lina; Yu, Bin; Sun, Gongqin

doi:10.3390/molecules24071363

Cited by 25 publications

(16 citation statements)

References 55 publications

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“…Our results showed that 9za could retard the cell population at G 0 /G 1 phase at low concentrations (<10 µM). Additionally, cell cycle arrest after 9za treatment could be explained by the decreased levels of CDK4, CDK6 and Cyclin D1, which are consistent with the previous literature (Liu et al, 2019a;Zhang et al, 2018). It is notable that when the concentration was less than or equal to 10 µM, 9za showed a trend of dose-dependent cell cycle arrest in G 0 /G 1 phase.…”

supporting

confidence: 89%

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

Liu

Chen

et al. 2020

PeerJ

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Background A novel dual MEK/PDK1 inhibitor named 9za has been synthesized by our research team. Preliminary study showed that 9za possessed potent cytotoxicity and proapoptosis in non-small cell lung cancer (NSCLC) cells. Nevertheless, the precise underlying mechanism is vague. Methods In this work, we adopted the MTT assay, the Cell Cycle Detection Kit, and the JC-1 staining assay to detect the cell viability, the cell cycle distribution and the mitochondrial membrane potential (MMP), respectively. Cell apoptosis was measured by the morphology observation under a light microscope, Annexin V-FITC/propidium iodide (PI) apoptosis detection and the colorimetric TUNEL assay. Western blot was used to monitor the cell cycle-, apoptosis-related proteins and relevant proteins involved in the signaling pathways. Results The MTT assay demonstrated that 9za sharply decreased the viability of NSCLC cells. Cell cycle analysis revealed that low concentrations of 9za arrested the cell cycle at the G0/G1 phase , which was further confirmed by the decreased levels of Cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). Additionally, morphological observations, Annexin V-FITC/propidium iodide (PI) apoptosis analysis and TUNEL assays indicated that high concentrations of 9za induced cell apoptosis. Furthermore, the JC-1 staining assay revealed that the mitochondrial membrane potential was downregulated following 9za exposure. Western blot also showed that 9za markedly decreased the expression levels of total Bcl-2, Cytochrome C in the mitochondria and BCL2 associated X (BAX) in the cytoplasm. However, the levels of BAX in the mitochondria, Cytochrome C in the cytoplasm, active caspase-9, active caspase-3 and cleaved–PARP showed the opposite changes. Moreover, the dose-dependent decreased phosphorylation levels of PDK1, protein kinase B (Akt), MEK and extracellular signal regulated kinase 1/2 (ERK1/2) after 9za treatment verified that 9za was indeed a dual MEK/PDK1 inhibitor, as we expected. Compared with a single MEK inhibitor PD0325901 or a single PDK1 inhibitor BX517, the dual MEK/PDK1 inhibitor 9za could strengthen the cytotoxic and proapoptotic effect, indicating that the double blocking of the MEK and PDK1 signaling pathways plays stronger cell growth inhibition and apoptosis induction roles than the single blocking of the MEK or PDK1 signaling pathway in NSCLC cells. Our work elucidated the molecular mechanisms for 9za as a novel drug candidate against NSCLC.

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confidence: 89%

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

Liu

Chen

et al. 2020

PeerJ

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“…One hypothesis would link necrotic cell death to a blockade of the cell cycle by the TKIs during progression from G1 to S phase. Interestingly, previous in vitro investigation reported a cell cycle arrest in the G1 phase in liver cancer cells treated with ponatinib, and identified that this cell cycle blockade was mediated by a reduction in the function of the CDK4/CDK6/Cyclin D1 complex ( Liu et al., 2019 ). This complex is regulated by the prosurvival PI3K/Akt pathway, known to be impacted by some BCR-ABL TKIs, including ponatinib ( Talbert et al., 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

Haguet

Bouvy²,

Delvigne³

et al. 2020

Front. Pharmacol.

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BCR-ABL tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia, inducing deep molecular responses, largely improving patient survival and rendering treatment-free remission possible. However, three of the five BCR-ABL TKIs, dasatinib, nilotinib, and ponatinib, increase the risk of developing arterial thrombosis. Prior investigations reported that nilotinib and ponatinib affect the endothelium, but the mechanisms by which they exert their toxic effects are still unclear. The impact of dasatinib and bosutinib on endothelial cells has been poorly investigated. Here, we aimed to provide an in vitro homogenous evaluation of the effects of BCR-ABL TKIs on the endothelium, with a special focus on the type of cell death to elucidate the mechanisms responsible for the potential cytotoxic effects of BCR-ABL TKIs nilotinib and ponatinib on endothelial cells. We tested the five BCR-ABL TKIs at three concentrations on human umbilical venous endothelial cells (HUVECs). This study highlights the endothelial toxicity of ponatinib and provides insights about the mechanisms by which it affects endothelial cell viability. Ponatinib induced apoptosis and necrosis of HUVECs after 72 h. Dasatinib affected endothelial cells in vitro by inhibiting their proliferation and decreased wound closure as soon as 24 h of treatment and even at infra-therapeutic dose (0.005 µM). Comparatively, imatinib, nilotinib, and bosutinib had little impact on endothelial cells at therapeutic concentrations. They did not induce apoptosis nor necrosis, even after 72 h of treatment but they inhibited HUVEC proliferation. Overall, this study reports various effects of BCR-ABL TKIs on endothelial cells and suggests that ponatinib and dasatinib induce arterial thrombosis through endothelial dysfunction.

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“…Several studies have reported that PDK1 regulates cellular metabolism by activating the AKT/mTOR pathway (30)(31)(32). Adenoviral -PDK1 construct or adenoviral -NC construct was transduced into MC3T3-E1 cells before exposure to dexamethasone.…”

Section: Figure 4 | Upregulation Of Pdk1 Promoted the Osteogenic Abilmentioning

confidence: 99%

HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway

Zheng

Yang

et al. 2020

Front. Endocrinol.

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Long-term and high dose glucocorticoid treatment can cause decreased viability and function of osteoblasts, which leads to osteoporosis and osteonecrosis. In this study, we investigated the role and mechanism of action of HIF-1α in glucocorticoid-induced osteogenic inhibition in MC3T3-E1 cells. Our results showed that HIF-1α protein expression was reduced when MC3T3-E1 cells were exposed to dexamethasone (Dex) at varying concentrations ranging from 10 −9 to 10 −6 M. PDK1 expression was also decreased in MC3T3-E1 cells after dexamethasone treatment. MC3T3-E1 cells when treated with the glucocorticoid receptor antagonist RU486 along with dexamethasone showed enhanced HIF-1α expression. In addition, upregulated expression of HIF-1α was capable of promoting the osteogenic ability of MC3T3-E1 cells and PDK1 expression. However, the HIF-1α antagonist 2-methoxyestradiol (2-ME) had a reverse effect in MC3T3-E1 cells exposed to dexamethasone. Furthermore, the PDK1 antagonist dichloroacetate could repress the osteogenic ability of MC3T3-E1 cells, although HIF-1α was upregulated when transduced with adenovirus-HIF-1α construct. The PDK1 agonist PS48 was able to promote the osteogenic ability of MC3T3-E1 cells treated with dexamethasone. Importantly, the protein levels of p-AKT and p-mTOR were increased in MC3T3-E1 cells treated with dexamethasone after PS48 treatment. in vivo, the PDK1 agonist PS48 could maintain the bone mass of mice treated with dexamethasone. This study provides a new understanding of the mechanism of glucocorticoid-induced osteoporosis.

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Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Cited by 25 publications

References 55 publications

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway

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Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

Cited by 25 publications

References 55 publications

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G0/G1 phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G0/G1 phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study

HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway

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A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells

A novel dual MEK/PDK1 inhibitor 9za retards the cell cycle at G₀/G₁ phase and induces mitochondrial apoptosis in non-small cell lung cancer cells