Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase

Yang, Kaiyin; Wu, Canrong; Zheng, Mengzhu; Tang, Ruotian; Li, Xingzhou; Chen, Lixia; Li, Hua

doi:10.1016/j.bioorg.2019.103186

Cited by 17 publications

(9 citation statements)

References 39 publications

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“…As glutamine metabolism is enhanced in most cancers, many potent small-molecule inhibitors have been developed to target GLS1, including CB-839 and the selenadiazole-derivatives CPD-20, CPD-23, and physapubescin I [ 32 , 43 , 44 ]. CB-839, which was used in the present study, is known to have broad anticancer activity and currently remains under evaluation in dozens of clinical trials [ 32 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Lang

Wang

Ding

et al. 2021

J Exp Clin Cancer Res

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Background Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. Methods A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate. Results We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. Conclusions These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

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Section: Discussionmentioning

confidence: 99%

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Lang

Wang

Ding

et al. 2021

J Exp Clin Cancer Res

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“…Another widely used glutaminase inhibitor is compound 968, a dibenzophenanthridine, which is first reported to be a GAC inhibitor and repressed oncogenic transformation in breast cancer cells, but is lately found by Lukey et al to be a panglutaminase inhibitor with a moderate selectivity for GLS2 (65, 78). Recently, more potent GLS inhibitors were investigated, including CB-839 selenadiazole-derivatives CPD-20, CPD-23 (131), and Physapubescin I (132). Structures of selected inhibitors and the allosteric binding of GLS1 with BPTES and CB-839 are shown in Figure 3 (66).…”

Section: Glutaminase Inhibitor Based Therapeutic Strategymentioning

confidence: 99%

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

et al. 2020

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Metabolism rewiring is an important hallmark of cancers. Being one of the most abundant free amino acids in the human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, and the production of antioxidants through glutaminolysis in cancers. In glutamine dependent cancer cells, more than half of the tricarboxylic/critic acid (TCA) metabolites are derived from glutamine. Glutaminolysis controls the process of converting glutamine into TCA cycle metabolites through the regulation of multiple enzymes, among which the glutaminase shows the importance as the very first step in this process. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Here, we review the regulation of glutaminase and the role of glutaminase in cancer metabolism and metastasis. Furthermore, we highlight the glutaminase inhibitor based metabolic therapy strategy and their potential applications in clinical scenarios.

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“…In addition, as the binding affinities of these compounds are reduced with increasing enzyme concentration, characterization methods which require high protein concentrations, such as isothermal titration calorimetry, or surface plasmon resonance, are not ideal for studying this class of glutaminase inhibitors. A newer technique, microscale thermophoresis, might offer an alternative as it requires less protein for measurement [ 73 ], but to the best of our knowledge no such study has yet been attempted.…”

Section: Molecular Basis For Glutaminase Inhibitionmentioning

confidence: 99%

“…caused the enzyme to reduce aggregation), C9 did not exhibit such an effect. Natural-product inhibitors have also been identified, including physapubescin [ 73 ] and brachyantheraoside A8 [ 79 ]. Interestingly, physapubescin shares structural similarity with the benzophenathridinone class of inhibitors, displaying even lower IC 50 .…”

Section: Molecular Basis For Glutaminase Inhibitionmentioning

confidence: 99%

Alone and Together: Current Approaches to Targeting Glutaminase Enzymes As Part of Anti-Cancer Therapies

Nguyen

Katt

Cerione

2022

Future Drug. Discov.

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Metabolic reprogramming is a major hallmark of malignant transformation in cancer, and part of the so-called Warburg effect, in which the upregulation of glutamine catabolism plays a major role. The glutaminase enzymes convert glutamine to glutamate, which initiates this pathway. Inhibition of different forms of glutaminase (KGA, GAC, or LGA) demonstrated potential as an emerging anti-cancer therapeutic strategy. The regulation of these enzymes, and the molecular basis for their inhibition, have been the focus of much recent research. This review will explore the recent progress in understanding the molecular basis for activation and inhibition of different forms of glutaminase, as well as the recent focus on combination therapies of glutaminase inhibitors with other anti-cancer drugs.

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Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase

Cited by 17 publications

References 39 publications

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Alone and Together: Current Approaches to Targeting Glutaminase Enzymes As Part of Anti-Cancer Therapies

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