AMPK: Therapeutic Target for Diabetes and Cancer Prevention

Umezawa, Shotaro; Higurashi, Takuma; Nakajima, Atsushi

doi:10.2174/0929867324666170713150440

Cited by 42 publications

(34 citation statements)

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“…The ATK–mTOR pathway has been considered to play a critical role in autophagy regulation in previous studies. 18 – 21 Perifosine, 22 a chemical reagent preventing AKT phosphorylation and activation, was used to investigate whether the ATK–mTOR pathway is involved in the autophagy-inhibiting process of DCA. Cells were cotreated with DCA and perifosine for 24 h. Cell apoptosis was almost reduced by half in the coincubation group compared with the DCA treatment group, which is consistent with the cell viability assays ( Figure 3A and B, D and E , p <0.05).…”

Section: Resultsmentioning

confidence: 99%

Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer

Xiao¹,

Zhou²,

Hou³

et al. 2018

CMAR

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BackgroundChemotherapy is still the primary adjuvant strategy of cancer therapy; however, the emergence of multi-drug resistance has been a cause for concern. Autophagy has been demonstrated to have a protective role against chemotherapeutic drugs in cancer cells, and autophagy inhibition is generally considered to be a promising therapeutic strategy. However, the paucity of effective and specific autophagy inhibitors limits its application.PurposeThe objective of this study was to explore the effect of DCA, small molecular anti-tumor agent, on the autophagy regulation and chemosensitization in NSCLC cells.MethodsWe investigated the autophagy regulation of dichloroacetate (DCA) by laser confocal microscopy and western blotting in A549 and H1975 cell lines. The MTT assay and flow cytometry was performed for explore the chemosensitization effectiveness of DCA. The results were verified with subcutaneous tumor model in nude mice and the immunohistochemistry was applied for assessing the level of cell apoptosis and autophagy in vivo post treatment.ResultsWe found that DCA, which exhibited antitumor properties in various carcinoma models, induced apoptosis of non-small cell lung cancer cells (NSCLC) by inhibiting cancer cell autophagy. Furthermore, Perifosine, an AKT inhibitor, can greatly weaken the capacity of inducing apoptosis by DCA. The results indicate that the AKT-mTOR pathway, a main negative regulator of autophagy, is involved in the DCA-induced inhibition of autophagy. Then, we detected the effectiveness of autophagy inhibition by DCA. When used in co-treatment with the chemotherapeutic drug paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited proliferation in A549 and H1975 cells. The results of the xenograft experiment demonstrate that co-treatment of PTX and DCA can significantly decrease cell proliferation in vivo and prolong the survival of mice.ConclusionOur results suggest that DCA can inhibit cell autophagy induced by chemotherapeutics, providing a new avenue for cancer chemotherapy sensitization.

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Section: Resultsmentioning

confidence: 99%

Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer

Xiao¹,

Zhou²,

Hou³

et al. 2018

CMAR

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“…Various conditions can stimulate AMPK in the body, such as calorie restriction, which depresses cellular energy supplies and triggers AMPK. This is the reason that calorie constraint has been detected to diminish malignancy occurrence and augment cancer cell death in animal models (15)(16)(17)(18).…”

Section: Methodsmentioning

confidence: 99%

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

Hooshyar¹,

Tolouian²,

Ghasemi³

et al. 2019

Immunopathol Persa

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Chemotherapeutic agents are still the major and most common therapy to prevent tumor growth. These drugs have various adverse effects in different organs in addition to systemic effects. Finding more specific and effective drugs or new adjuvant therapeutic substance is needed to improve the success rate. Several studies have proposed the possible mechanisms of anti-neoplastic of metformin, however, its exact mechanism is still obscure. The suggested mechanisms are; alteration in the host metabolic environment after administration of metformin, such as decreases in insulin-dependent stimulation of tumor growth or direct effect on cancer cells, such as the impact on adenosine monophosphate (AMP)-activated protein kinase signaling pathway. Metformin, as an adjuvant therapy, synergistically exerts growth inhibitory effects against cell growth and can induce cell apoptosis in an animal model. Adding metformin to the chemotherapy regimen may reduce resistance and enhance therapeutic efficacy.

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“…In view of the essential role of AMPK in different cellular processes, it is not surprising that several pathologies including cancer, metabolic dysfunction, in ammatory disorders and neurodegeneration have been associated with this kinase [3,[9][10][11]. Concerning cancer, pro-tumorigenic and tumor suppressor functions have been reported for AMPK, depending on parameters such as subcellular location, complex members and upstream modulators [12].…”

Section: Introductionmentioning

confidence: 99%

“…Activated AMPK induces autophagy, promotes mitochondrial biogenesis and is involved in apoptosis [18,20,21], thereby fostering prostate cancer growth and survival, whereas silencing AMPK expression reduces prostate cancer cell proliferation and migration [13,22]. However, other studies report that AMPK has a tumor suppressor role in prostate cancer [19,[23][24][25], so that potent and selective chemical probes [26] will be essential to understand the enigmatic function of AMPK in cancer and other pathologies [2,3,9,12]. AMPK activators mainly bind to the allosteric drug and metabolite site located at the α/β subunit interface and have different isoform selectivity [11].…”

Section: Introductionmentioning

confidence: 99%

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

Lemos

Schulze

Baumgart

et al. 2020

Preprint

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Background: 5´ adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis which has been associated with different pathologies, including cancer. Precisely defining the role of AMPK in these processes necessitates the availability of a potent and selective inhibitor.Methods: High-throughput screening and subsequent chemical optimization led to the identification of the selective inhibitor BAY-3827. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact of BAY-3827 and the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation.Results: BAY-3827 prevented phosphorylation of acetyl-CoA carboxylase 1 and showed strongest anti-proliferative activity in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive prostate cancer cell lines. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified androgen receptor (AR) binding peaks in these genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in the responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux.Conclusions: The availability of the potent and selective inhibitor BAY-3827 will contribute to a better understanding of the biological role of AMPK signaling in cancer, especially in prostate adenocarcinoma.

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AMPK: Therapeutic Target for Diabetes and Cancer Prevention

Cited by 42 publications

References 0 publications

Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer

Dichloroacetate enhances the antitumor efficacy of chemotherapeutic agents via inhibiting autophagy in non-small-cell lung cancer

Administration of metformin to increase the efficacy of chemotherapy regimen in cancers; a new look to an old drug

The Potent and Selective AMPK Inhibitor BAY-3827 Shows Strong Efficacy in Androgen-Dependent Prostate Cancer Models

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