Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase

Ning, Xianling; Qi, Hailong; Li, Ridong; Li, Yunqiao; Jin, Yan; McNutt, Michael A.; Liu, Junyi; Yin, Yuxin

doi:10.1016/j.ejmech.2017.06.064

Cited by 83 publications

(59 citation statements)

References 24 publications

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“…Since PKM2 is a pyruvate kinase, the activator DASA 58 was able to elevate its enzymatic activity but inhibit its expression, and the inhibitor compound 3 K was able to reduce the enzymatic activity of PKM2 but promote its expression. Therefore after treatment with compound 3 K (3 μM) [40], the expression of PKM2 was up-regulated, whereas the expression of HIF-1α and PPAR-γ were found to be the same as the CTRL group. However, if compound 3 K was cotreated with Sora + Sim, the up-regulation of PKM2 was decreased slightly, and the expression of HIF-1α and PPAR-γ remained the same as the Sora + Sim group.…”

Section: Sim Enhances the Sensitivity Of Sora By Down-regulating The mentioning

confidence: 86%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

149

127

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

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Section: Sim Enhances the Sensitivity Of Sora By Down-regulating The mentioning

confidence: 86%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

149

127

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“…There are many small molecule inhibitors and hormones that inhibit cell proliferation by targeting PKM2 (77)(78)(79). The inhibitors, namely shikonin and its analogs, flavonoid derivatives, and 2,3-dithiocarbamate substituted naphthoquinones bind to the allosteric site of PKM2, which leads to reduced glycolysis in cancer cells (77,(80)(81)(82).…”

Section: Pkm2 As a Potential Target For Cancer Therapymentioning

confidence: 99%

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

et al. 2020

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Pyruvate kinase plays a pivotal role in regulating cell metabolism. The final and rate-limiting step of glycolysis is the conversion of Phosphoenolpyruvate (PEP) to Pyruvate, which is catalyzed by Pyruvate Kinase. There are four isomeric, tissue-specific forms of Pyruvate Kinase found in mammals: PKL, PKR, PKM1, and PKM2. PKM1 and PKM2 are formed bya single mRNA transcript of the PKM gene by alternative splicing. The oligomers of PKM2 exist in high activity tetramer and low activity dimer forms. The dimer PKM2 regulates the rate-limiting step of glycolysis that shifts the glucose metabolism from the normal respiratory chain to lactate production in tumor cells. Besides its role as a metabolic regulator, it also acts as protein kinase, which contributes to tumorigenesis. This review is focused on the metabolic role of pyruvate kinase M2 in normal cells vs. cancerous cells and its regulation at the transcriptional level. The review also highlights the role of PKM2 as a potential diagnostic marker and as a therapeutic target in cancer treatment.

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“…By using library screening, Vander Heiden et al identified three novel classes of PKM2 inhibitors and showed that the most effective compound inhibited PKM2 activity and induced death of cancer cells [ 31 ]. Recently, Ning et al found that novel naphthoquinone derivatives are potent PKM2 inhibitors [ 87 ]. One effective compound 3 k suppressed the proliferation of multiple cancer cell lines at sub-micromolar concentrations while it showed little detrimental effect on normal cells.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling

2018

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Originally identified as a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP in the glycolytic pathway, pyruvate kinase M2-type (PKM2) has been shown to exhibit novel biological activities in the nucleus and outside the cells. Although cell-based studies reveal new non-canonical functions of PKM2 in gene transcription, epigenetic modulation and cell cycle progression, the importance of these non-canonical functions in PKM2-mediated tumorigenesis is still under debate because studies in genetically modified mice do not consistently echo the findings observed in cultured cancer cells. In addition to regulation of gene expression, the existence of PKM2 in exosomes opens a new venue to study the potential role of this glycolytic enzyme in cell-cell communication and extracellular signal initiation. In this review, we briefly summarize current understanding of PKM2 in metabolic switch and gene regulation. We will then emphasize recent progress of PKM2 in extracellular signaling and tumor microenvironment reprogramming. Finally, the discrepancy of some PKM2’s functions in vitro and in vivo, and the application of PKM2 in cancer detection and treatment will be discussed.

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Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase

Cited by 83 publications

References 24 publications

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling

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