scholarly journals Cytoophidium assembly reflects upregulation of IMPDH activity

2015 ◽  
Vol 128 (19) ◽  
pp. 3550-3555 ◽  
Author(s):  
C.-C. Chang ◽  
W.-C. Lin ◽  
L.-M. Pai ◽  
H.-S. Lee ◽  
S.-C. Wu ◽  
...  
Keyword(s):  
Impdh Activity

scholarly journals Expression of IMP dehydrogenase in differentiating HL-60 cells

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 570-576 ◽  
Author(s):  
FR Collart ◽  
E Huberman
Keyword(s):  
Cell Differentiation ◽  
Mycophenolic Acid ◽  
Messenger Rna ◽  
Cellular Level ◽  
Imp Dehydrogenase ◽  
Protein Levels ◽  
Impdh Activity ◽  
Subsequent Decrease ◽  
Number Of Factors ◽  
Steady State Levels

Abstract Addition of mycophenolic acid to cultures of HL-60 cells results in a decreased cellular level of guanine nucleotides and the induction of cell differentiation. During the early stages of this induction, steady- state levels of cellular IMP dehydrogenase (IMPDH), messenger RNA (mRNA), and protein are increased, perhaps because of cellular compensation for the inhibition of IMPDH activity. The subsequent decrease in IMPH mRNA and protein levels after several days of treatment suggests a change in the control of IMPDH expression. In contrast to the pattern of increased IMPDH expression observed in the mycophenolic acid-treated cells, treatment of HL-60 cells with two other inducers of differentiation, namely retinoic acid and phorbol 12- myristate 13-acetate, resulted in stable or decreased levels of cellular IMPDH mRNA and protein. However, the kinetics of this expression were different. These results suggest that a number of factors influence the regulation of IMPDH expression during the induction of HL-60 cell differentiation, including the nature of the inducer. A decrease in the cellular IMPDH activity was observed for all of the inducers, suggesting that this decreased activity may be a determining factor in the acquisition of a mature phenotype in the HL- 60 cells.

scholarly journals IMP/GTP balance modulates cytoophidium assembly and IMPDH activity

Cell Division ◽  
2018 ◽  
Vol 13 (1) ◽  
Author(s):  
Gerson Dierley Keppeke ◽  
Chia Chun Chang ◽  
Min Peng ◽  
Li-Yu Chen ◽  
Wei-Cheng Lin ◽  
...  
Keyword(s):  
Impdh Activity

Clinical-Biomarker Correlations in Adult AML Patients in a Phase I Trial of AVN944 Support Observations of Clinical Effect and Provide Hypotheses for Patient Selection Criteria for Further Clinical Trials.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 896-896 ◽  
Author(s):  
Rebecca B. Klisovic ◽  
Steven Coutre ◽  
Tibor J. Kovacsovics ◽  
Hagop M. Kantarjiam ◽  
Guido J. Tricot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stable Disease ◽  
Peripheral Blood ◽  
Drug Binding ◽  
Metabolic Effects ◽  
Phase Cell ◽  
Phase Ii Trials ◽  
Impdh Activity ◽  
Dose Levels

Abstract Background: AVN944 is an uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) that catalyzes the rate limiting step in the synthesis of guanine nucleotides. In vitro studies have demonstrated its efficacy in inducing apoptosis in leukemic cell lines. Between 01/06 and 7/07 a total of 117 cycles of AVN944 were administered to 50 patients (pts) with advanced hematologic malignancies (AML = 26, multiple myeloma = 15, CLL = 6, ALL = 2, and NHL = 1) at dose levels of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, and 250 mg bid po x 21d every 28 d. The study employed open label dose escalation with safety, pK, IMPDH activity, gene expression biomarkers, & efficacy endpoints. Biomarker evaluations in AML pts were most useful since AML blasts could be obtained from the peripheral blood in most subjects. Results: Pharmacokinetics corresponded to dose levels over the dose range tested with a Tmax = 1 hour, T1/2 of 1.5 hours, a mean Cmax=4060 ng/ml and AUC=12146hr*ng/ml at the 200 mg bid dose. Toxicities were generally mild-moderate and/or attributable to the underlying disease. Twenty-four SAEs were observed in 16 pts (10 w/AML; 4 w/CLL, 1w/MM, 1w/ALL). Twenty-two of the SAEs were felt to be unrelated to AVN944; 1 AVN944-related SAE/DLT was observed at both the 150 mg bid (dizziness and fever) and at the 200 mg bid (UGI mucositis w/bleeding) levels, prompting expansion of the accrual to those dose levels. Additional DLTs were not seen. Among AML pts, no protocol-defined responses were seen, but 9 of 26 pts had stable disease of 2 to 9 months’ duration. Peripheral blood mononuclear cell (mean blast percentage 78%) were obtained from all pts before and after receiving AVN944 to determine drug effects on IMPDH enzyme activity (GTP pools) and modulation of 34-gene expression biomarkers that reflect cellular and metabolic effects of AVN944, including inhibition of IMPDH activity, depletion of GTP pools, G1/S phase cell-cycle block, and apoptosis. At the highest doses tested, Western blots show IMPDH-drug binding for at least 4 hours and depletion of GTP pools relative to baseline for at least 8 hours (last time point tested). Gene expression-based biomarkers show a dynamic response in patient samples with a strong correlation of changes in gene expression with GTP pool depletion and clinically stable disease. Specifically, genes involved in cell cycle and cell division (RRM2 & ZWINT), GTP function (GNAQ & PDE7A), and apoptotic signaling (PIM1) change 2–4 fold after drug exposure compared to baseline measurements. Further, in pts naïve to AVN944 therapy, expression of genes related to drug metabolism, drug resistance and apoptosis predict for biochemical activity of AVN944. Based on these data, algorithms were applied retrospectively to define a set of gene expression biomarkers for enrichment for patients more likely to benefit from drug. This set of biomarkers will be validated for their sensitivity and specificity in identifying the most appropriate patient population in upcoming phase II trials.

Serum Metabolomics Uncovers a New Therapeutic Target in Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1648-1648
Author(s):  
Leandro Cerchietti ◽  
Chen Qiuying ◽  
ShaoNing Yang ◽  
Wang Chunjie ◽  
Steven Gross
Keyword(s):  
Cell Lines ◽  
B Cell Lymphoma ◽  
Hsp90 Inhibitor ◽  
Metabolic Changes ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Impdh Activity ◽  
Client Proteins ◽  
Serum Metabolomics ◽  
Impdh Inhibitors

Abstract Abstract 1648 DLBCL is a molecularly heterogeneous disease usually treated with chemoimmunotherapy ultimately curing ∼65% of pts. In order to improve therapy for these pts, the identification of broadly relevant therapeutic targets is critical. One such target is HSP90. Tumor cells are enriched for a fraction of HSP90 found in higher-order multi-chaperone complexes. Tumor-enriched HSP90 (teHSP90) displays higher affinity for HSP90 inhibitors than normal tissues, which contain latent, uncomplexed HSP90. Many client proteins are depleted upon exposure to teHSP90 inhibitors. PU-H71 is a highly teHSP90 selective inhibitor with an excellent toxicity profile currently being tested for DLBCL in clinical trials. Combination therapies involving teHSP90 inhibitors may synergize with drugs targeting client proteins of teHSP90 by more powerfully inhibit survival pathways. Cell replication involves substantial metabolic demands and PU-H71-induced degradation of enzymatic client proteins may affect critical metabolic pathways. We hypothesized that by identifying PU-H71-induced metabolic changes, metabolomics could point to potential new targets for combinatorial therapeutic intervention. We therefore analyzed the global metabolic consequence of teHSP90 inhibition in DLBCL by PU-H71. The metabolome was analyzed in the serum of LY7 DLBCL xenografted mice treated with 75 mg/m2 of PU-H71 for 24 h (n=5) or vehicle (n=5) by HPLC/MS. Bioinformatic analysis revealed significant changes in 122 metabolites in PUH-71- vs. vehicle-treated mice; including significantly lower levels of xanthine, hypoxanthine, adenosine, xanthosine monophosphate (XMP), depletion of the guanine nucleoside pool, together with higher levels of inosine and inosine monophosphate (IMP). These metabolic changes pointed towards possible PU-H71 mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). IMPDH catalyzes the NAD-dependent oxidation of IMP to XMP, which is the committed step in de novo guanosine nucleotide biosynthesis. This reaction is particularly important to lymphocytes, which depend on IMPDH activity to generate the guanosine nucleotide levels needed to initiate a proliferative response to antigen. Increased IMPDH activity has also been observed in leukemia and lymphoma, mostly as consequence of up-regulation of the IMPDH2 isoform. In order to determine whether IMPDH1/2 stability depends on teHSP90, we treated a panel of 6 DLBCL cell lines (including LY7) with the mean GI50 of PU-H71 (1 μM) for up to 24 h and checked for IMPDH1/2 abundance. We found a time-dependent decrease in IMPDH2 protein levels. Similar results were obtained with the chemically unrelated HSP90 inhibitor 17-DMAG. To confirm that IMPDH2 binds to teHSP90, we took advantage of an affinity-based PUH-71 pull-down method we recently developed. In this assay PU-H71-beads preferentially bind to teHSP90 complexes pecipitating cancer-related client proteins. By using this assay, we determined that IMPDH2 was indeed a teHSP90 client in DLBCL cells. We also found that PU-H71 (and 17-DMAG) inhibited the activity of IMPDH in DLBCL cells by shortening its half-live (IMPDH t1/2from 2 h to 45 min). To determine whether the combination of teHSP90 inhibitors will synergize with IMPDH inhibitors in killing DLBCL, we treated a panel of 10 DLBCL cell lines with the combination of PU-H71 and two IMPDH inhibitors in clinical use, mycophenolic acid (MPA, an uncompetitive inhibitor) and ribavirin (RIB, a competitive inhibitor). We found that most cell lines showed synergistic killing effect when treated with the combination of drugs compared to each drug alone (determined by isobologram method). This prompted us to test the combination in vivo. SCID mice were xenografted with LY7 and SUDHL6 and once tumor developed, they were treated with vehicle, PU-H71, mycophenolate mofetil (MMF, the pro-drug of MPA), RIB and the combination of PU-H71 and MMF or RIB. We found that mice treated with the combination of drugs exhibited greater effect that each drug alone (p=0.002 for SU-DHL6 and p>0.001 for LY7 for PU-H71+MMF, and p=0.01 for SU-DHL6 and p=0.02 for LY7 for PU-H71+RIB, all T-test day 10). There were no toxic effects. In sum, our work uses serum metabolomics to provide new insights into the pharmacological targets of a particular HSP90 inhibitor, and unveiled a critical survival pathway in DLBCL that was harnessed to develop a rationally combined targeted therapy. Disclosures: No relevant conflicts of interest to declare.

DETERMINATION OF IMPDH ACTIVITY IN WHOLE BLOOD: VALIDATION OF OUR ASSAY.

1999 ◽  
Vol 21 (4) ◽  
pp. 446
Author(s):  
S. Sanquer ◽  
M. Breil ◽  
C. Baron ◽  
D. Dhamane ◽  
P. Lang ◽  
...  
Keyword(s):  
Whole Blood ◽  
Impdh Activity

PHARMACODYNAMIC MONITORING OF MYCOPHENOLATE MOFETIL BY MEASUREMENT OF IMPDH ACTIVITY.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S134 ◽  
Author(s):  
Klemens Budde ◽  
Petra Glander ◽  
Lutz Fritsche ◽  
Johannes Waiser ◽  
Steffen Bauer ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Impdh Activity

INDUCTION OF IMPDH ACTIVITY AFTER LONG-TERM TREATMENT WITH MYCOPHENOLATE MOFETIL

1998 ◽  
Vol 65 (Supplement) ◽  
pp. 122
Author(s):  
S. Sanquer ◽  
M. Breil ◽  
Ph. Baron ◽  
D. Dhamane ◽  
A. Astier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Term Treatment ◽  
Impdh Activity ◽  
Long Term Treatment

INDUCTION OF IMPDH ACTIVITY AFTER LONG-TERM TREATMENT WITH MYCOPHENOLATE MOFETIL

1998 ◽  
Vol 65 (12) ◽  
pp. S46
Author(s):  
S. Sanquer ◽  
M. Breil ◽  
Ph. Baron ◽  
D. Dhamane ◽  
A. Astier ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Term Treatment ◽  
Impdh Activity ◽  
Long Term Treatment
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