Background: Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839.
Methods: We analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models.
Results: Metabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media PlasmaxTM. In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors.
Conclusion: Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.
{"title":"Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma.","authors":"Sunada Khadka, Kenisha Arthur, Yasaman Barekatain, Eliot Behr, Mykia Washington, Jeffrey Ackroyd, Kaitlyn Crowley, Pornpa Suriyamongkol, Yu-Hsi Lin, Cong-Dat Pham, Rafal Zielinski, Marissa Trujillo, James Galligan, Dimitra K Georgiou, John Asara, Florian Muller","doi":"10.1186/s40170-021-00259-4","DOIUrl":"https://doi.org/10.1186/s40170-021-00259-4","url":null,"abstract":"<p><strong>Background: </strong>Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates and must be replenished (anaplerosis), mainly from pyruvate and glutamine. We recently described a novel enolase inhibitor, HEX, and its pro-drug POMHEX. Since glycolysis inhibition would deprive the cell of a key source of pyruvate, we hypothesized that enolase inhibitors might inhibit anaplerosis and synergize with other inhibitors of anaplerosis, such as the glutaminase inhibitor, CB-839.</p><p><strong>Methods: </strong>We analyzed polar metabolites in sensitive (ENO1-deleted) and resistant (ENO1-WT) glioma cells treated with enolase and glutaminase inhibitors. We investigated whether sensitivity to enolase inhibitors could be attenuated by exogenous anaplerotic metabolites. We also determined the synergy between enolase inhibitors and the glutaminase inhibitor CB-839 in glioma cells in vitro and in vivo in both intracranial and subcutaneous tumor models.</p><p><strong>Results: </strong>Metabolomic profiling of ENO1-deleted glioma cells treated with the enolase inhibitor revealed a profound decrease in the TCA cycle metabolites with the toxicity reversible upon exogenous supplementation of supraphysiological levels of anaplerotic substrates, including pyruvate. ENO1-deleted cells also exhibited selective sensitivity to the glutaminase inhibitor CB-839, in a manner rescuable by supplementation of anaplerotic substrates or plasma-like media Plasmax<sup>TM</sup>. In vitro, the interaction of these two drugs yielded a strong synergistic interaction but the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood-brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors.</p><p><strong>Conclusion: </strong>Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"9 1","pages":"27"},"PeriodicalIF":5.9,"publicationDate":"2021-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-021-00259-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9238754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1016/B978-0-12-405205-5.00003-9
W. Loke, Mann Ying Lim, C. Lewis, P. Thomas
{"title":"Oxidative stress in lung cancer","authors":"W. Loke, Mann Ying Lim, C. Lewis, P. Thomas","doi":"10.1016/B978-0-12-405205-5.00003-9","DOIUrl":"https://doi.org/10.1016/B978-0-12-405205-5.00003-9","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"09 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86503135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1016/B978-0-12-405205-5.00025-8
C. Parrado, Á. Juarranz, Y. Gilaberte, N. Philips, S. González
{"title":"Fern extract, oxidative stress, and skin cancer","authors":"C. Parrado, Á. Juarranz, Y. Gilaberte, N. Philips, S. González","doi":"10.1016/B978-0-12-405205-5.00025-8","DOIUrl":"https://doi.org/10.1016/B978-0-12-405205-5.00025-8","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"1 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83777882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1016/B978-0-12-405205-5.00018-0
Alexandra M. Fajardo, M. Bisoffi
{"title":"Curcumin analogs, oxidative stress, and prostate cancer","authors":"Alexandra M. Fajardo, M. Bisoffi","doi":"10.1016/B978-0-12-405205-5.00018-0","DOIUrl":"https://doi.org/10.1016/B978-0-12-405205-5.00018-0","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"37 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87530549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1016/B978-0-12-405205-5.00002-7
M. Shiota, A. Yokomizo, S. Naito
{"title":"Oxidative stress and prostate cancer","authors":"M. Shiota, A. Yokomizo, S. Naito","doi":"10.1016/B978-0-12-405205-5.00002-7","DOIUrl":"https://doi.org/10.1016/B978-0-12-405205-5.00002-7","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"6 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83905469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01DOI: 10.1016/B978-0-12-405205-5.00016-7
D. Kang, Sang Ah Lee
{"title":"Antioxidant vitamins and genetic polymorphisms in breast cancer","authors":"D. Kang, Sang Ah Lee","doi":"10.1016/B978-0-12-405205-5.00016-7","DOIUrl":"https://doi.org/10.1016/B978-0-12-405205-5.00016-7","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"216 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75029425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-11-26DOI: 10.1186/s40170-020-00232-7
H Furkan Alkan, Paul W Vesely, Hubert Hackl, Johannes Foßelteder, Daniel R Schmidt, Matthew G Vander Heiden, Martin Pichler, Gerald Hoefler, Juliane G Bogner-Strauss
Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD+/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.
Results: Low AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.
Conclusion: This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo.
{"title":"Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis.","authors":"H Furkan Alkan, Paul W Vesely, Hubert Hackl, Johannes Foßelteder, Daniel R Schmidt, Matthew G Vander Heiden, Martin Pichler, Gerald Hoefler, Juliane G Bogner-Strauss","doi":"10.1186/s40170-020-00232-7","DOIUrl":"https://doi.org/10.1186/s40170-020-00232-7","url":null,"abstract":"<p><strong>Background: </strong>Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD<sup>+</sup>/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.</p><p><strong>Results: </strong>Low AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.</p><p><strong>Conclusion: </strong>This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"8 1","pages":"26"},"PeriodicalIF":5.9,"publicationDate":"2020-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40170-020-00232-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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