Browsing by Subject "Asparaginase"

Now showing 1 - 5 of 5
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    As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid
    (Elsevier, 2018-02-06) Pavlova, Natalya N.; Hui, Sheng; Ghergurovich, Jonathan M.; Fan, Jing; Intlekofer, Andrew M.; White, Richard M.; Rabinowitz, Joshua D.; Thompson, Craig B.; Zhang, Ji; Pediatrics, School of Medicine
    When mammalian cells are deprived of glutamine, exogenous asparagine rescues cell survival and growth. Here we report that this rescue results from use of asparagine in protein synthesis. All mammalian cell lines tested lacked cytosolic asparaginase activity and could not utilize asparagine to produce other amino acids or biosynthetic intermediates. Instead, most glutamine-deprived cell lines are capable of sufficient glutamine synthesis to maintain essential amino acid uptake and production of glutamine-dependent biosynthetic precursors, with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine and increase tricarboxylic acid cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted medium in vitro and severely compromised the in vivo growth of tumor xenografts. These results suggest that the lack of asparaginase activity represents an evolutionary adaptation to allow mammalian cells to survive pathophysiologic variations in extracellular glutamine.
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    Asparagine, a critical limiting metabolite during glutamine starvation
    (Taylor & Francis, 2018-04-11) Jiang, Jie; Pavlova, Natalya N.; Zhang, Ji; Pediatrics, School of Medicine
    A challenge of targeting glutamine metabolism in cancer is that tumor cells develop various strategies to adapt to glutamine limitation. We found that asparagine plays a critical role in supporting protein synthesis during glutamine starvation, highlighting a possible approach to optimize the therapeutic efficacy of targeting glutamine metabolism in cancer.
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    Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia
    (Wiley, 2021-11) Schulte, Rachael; Hinson, Ashley; Huynh, Van; Breese, Erin H.; Pierro, Joanna; Rotz, Seth; Mixon, Benjamin A.; McNeer, Jennifer L.; Burke, Michael J.; Orgel, Etan; Pediatrics, School of Medicine
    Background: Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity. Methods: We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. Results: Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival. Conclusions: This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
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    Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
    (SpringerNature, 2017-04-28) Al-Baghdadi, Rana J. T.; Nikonorova, Inna A.; Mirek, Emily T.; Wang, Yongping; Park, Jinhee; Belden, William J.; Wek, Ronald C.; Anthony, Tracy G.; Department of Biochemistry and Molecular Biology, School of Medicine
    The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 -/-, and Atf4 -/- mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 +/- mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 -/- or Atf4 +/- mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 -/- mice treated with asparaginase.
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