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Pardee Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100001287","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Uncle Kory Foundation","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"The Larry Deaven Fellowship","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100004917","name":"CPRIT","doi-asserted-by":"crossref","award":["RP170067"],"award-info":[{"award-number":["RP170067"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Metab"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We analyzed polar metabolites in sensitive (<jats:italic>ENO1<\/jats:italic>-deleted) and resistant (<jats:italic>ENO1<\/jats:italic>-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Metabolomic profiling of <jats:italic>ENO1<\/jats:italic>-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. <jats:italic>ENO1-<\/jats:italic>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<jats:sup>TM<\/jats: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 <jats:italic>ENO1<\/jats:italic>-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Together, these data suggest that at least for <jats:italic>ENO1<\/jats:italic>-deleted gliomas, tumors in vivo\u2014unlike cells in culture\u2014show 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40170-021-00259-4","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T10:03:04Z","timestamp":1624615384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma"],"prefix":"10.1186","volume":"9","author":[{"given":"Sunada","family":"Khadka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenisha","family":"Arthur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasaman","family":"Barekatain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliot","family":"Behr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mykia","family":"Washington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Ackroyd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaitlyn","family":"Crowley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pornpa","family":"Suriyamongkol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hsi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong-Dat","family":"Pham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafal","family":"Zielinski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marissa","family":"Trujillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Galligan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitra K.","family":"Georgiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Asara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7568-2948","authenticated-orcid":false,"given":"Florian","family":"Muller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"issue":"5","key":"259_CR1","doi-asserted-by":"publisher","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","volume":"2","author":"RJ DeBerardinis","year":"2016","unstructured":"DeBerardinis RJ, Chandel NS. 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F.L.M. is an inventor on a patent covering the concept of targeting ENO1-deleted tumors with inhibitors of ENO2 (US patent 9,452,182 B2) and an inventor on a patent application describing the synthesis and utility of novel pro-drug inhibitors of enolase US 62\/797,315 (filed Jan. 27, 2019). F.L.M. and Y-H.L. are inventors on a patent application for the use of enolase inhibitors for the treatment of ENO1-deleted tumors (US patent 10,363,261 B2).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"27"}}