scholarly journals P11.35 Fluorine-18-labeled PET radiotracers for imaging tryptophan uptake and metabolism in brain tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii50-iii51
Author(s):  
O Muzik ◽  
F John ◽  
S Mittal ◽  
C Juhasz
Keyword(s):  
Amino Acid ◽  
Brain Tumors ◽  
Cell Lines ◽  
Kynurenine Pathway ◽  
Biological Characteristics ◽  
Key Enzymes ◽  
Pet Radiotracers ◽  
Uptake And Metabolism ◽  
Tryptophan Uptake

Abstract BACKGROUND Abnormal metabolism of tryptophan via the serotonin and kynurenine pathways plays a key role in multiple disease processes including cancer. Upregulation of key enzymes of the kynurenine pathway (such as indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]) plays an important role in immune resistance in human brain tumors. IDO inhibitors have recently entered in human clinical trials, and their use can benefit from molecular imaging evaluating IDO activity. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative PET radiotracers. Human studies with such tracers showed promise but have been confined to carbon-11-labeled compounds (such as alpha-[11C]methyl-L-tryptophan). Preclinical development of fluorine-18-labeled tryptophan-based radiotracers has surged only in recent years. We performed a systematic review of studies reporting on such tracers and summarized their biological characteristics and their potential for imaging key enzymes of the kynurenine pathway. MATERIAL AND METHODS A PubMed search using the key words “tryptophan” and “PET”/”positron emission tomography” was performed. English language original articles including data on the preparation and/or radiochemical or biological characteristics of fluorine-18-labeled tryptophan derivative radiotracers have been reviewed. RESULTS Nineteen original papers identified by the search included data on 15 unique fluorine-18-labeled tryptophan-derived radiotracers. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer among the 15. Biodistribution studies showed high uptake in the pancreas, and the L-type amino acid transporter was the dominant transport mechanism for most of the reported radiotracers. Multiple tracers showed accumulation in various tumor cell lines, including glioma cell lines, in vitro and in xenografts in vivo, with favorable tumor-to-background uptake ratios in comparison to clinically used fluorine-18-labeled radiotracers (such as glucose and non-tryptophan amino acid analogs). Five of the 15 tracers showed promise for imaging IDO activity, including a fluorine-18-labeled analog of alpha-[11C]methyl-L-tryptophan. Two of the 15 radiotracers were metabolized by TDO but showed rapid defluorination in vivo. CONCLUSION Most fluorine-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several of these radiotracers show promise for imaging IDO activity in vivo, and, therefore, could be leading candidates for testing and validation toward human tumor PET imaging applications.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals Pretreatment Effect of Inflammatory Stimuli and Characteristics of Tryptophan Transport on Brain Capillary Endothelial (TR-BBB) and Motor Neuron Like (NSC-34) Cell Lines

Biomedicines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 9
Author(s):  
Asmita Gyawali ◽  
Young-Sook Kang
Keyword(s):  
Amino Acid ◽  
Motor Neuron ◽  
Cell Lines ◽  
Amino Acid Transporter ◽  
Mutant Type ◽  
Brain Capillary ◽  
Neuroprotective Drugs ◽  
Acid Transporter ◽  
Tryptophan Uptake ◽  
Tryptophan Transport

Tryptophan plays a key role in several neurological and psychiatric disorders. In this study, we investigated the transport mechanisms of tryptophan in brain capillary endothelial (TR-BBB) cell lines and motor neuron-like (NSC-34) cell lines. The uptake of [3H]l-tryptophan was stereospecific, and concentration- and sodium-dependent in TR-BBB cell lines. Transporter inhibitors and several neuroprotective drugs inhibited [3H]l-tryptophan uptake by TR-BBB cell lines. Gabapentin and baclofen exerted a competitive inhibitory effect on [3H]l-tryptophan uptake. Additionally, l-tryptophan uptake was time- and concentration-dependent in both NSC-34 wild type (WT) and mutant type (MT) cell lines, with a lower transporter affinity and higher capacity in MT than in WT cell lines. Gene knockdown of LAT1 (l-type amino acid transporter 1) and CAT1 (cationic amino acid transporter 1) demonstrated that LAT1 is primarily involved in the transport of [3H]l-tryptophan in both TR-BBB and NSC-34 cell lines. In addition, tryptophan uptake was increased by TR-BBB cell lines but decreased by NSC-34 cell lines after pro-inflammatory cytokine pre-treatment. However, treatment with neuroprotective drugs ameliorated tryptophan uptake by NSC-34 cell lines after inflammatory cytokines pretreatment. The tryptophan transport system may provide a therapeutic target for treating or preventing neurodegenerative diseases.

scholarly journals Phosphorylation of UT-A1 on serine 486 correlates with membrane accumulation and urea transport activity in both rat IMCDs and cultured cells

2010 ◽  
Vol 298 (4) ◽  
pp. F935-F940 ◽  
Author(s):  
Janet D. Klein ◽  
Mitsi A. Blount ◽  
Otto Fröhlich ◽  
Chad E. Denson ◽  
Xiaoxiao Tan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Amino Acid ◽  
Cell Lines ◽  
Specific Antibody ◽  
Cultured Cells ◽  
Apical Plasma Membrane ◽  
Wild Type ◽  
Amino Acid Peptide ◽  
In The Wild

Vasopressin is the primary hormone regulating urine-concentrating ability. Vasopressin phosphorylates the UT-A1 urea transporter in rat inner medullary collecting ducts (IMCDs). To assess the effect of UT-A1 phosphorylation at S486, we developed a phospho-specific antibody to S486-UT-A1 using an 11 amino acid peptide antigen starting from amino acid 482 that bracketed S486 in roughly the center of the sequence. We also developed two stably transfected mIMCD3 cell lines: one expressing wild-type UT-A1 and one expressing a mutated form of UT-A1, S486A/S499A, that is unresponsive to protein kinase A. Forskolin stimulates urea flux in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. The phospho-S486-UT-A1 antibody identified UT-A1 protein in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. In rat IMCDs, forskolin increased the abundance of phospho-S486-UT-A1 (measured using the phospho-S486 antibody) and of total UT-A1 phosphorylation (measured by 32P incorporation). Forskolin also increased the plasma membrane accumulation of phospho-S486-UT-A1 in rat IMCD suspensions, as measured by biotinylation. In rats treated with vasopressin in vivo, the majority of the phospho-S486-UT-A1 appears in the apical plasma membrane. In summary, we developed stably transfected mIMCD3 cell lines expressing UT-A1 and an S486-UT-A1 phospho-specific antibody. We confirmed that vasopressin increases UT-A1 accumulation in the apical plasma membrane and showed that vasopressin phosphorylates UT-A1 at S486 in rat IMCDs and that the S486-phospho-UT-A1 form is primarily detected in the apical plasma membrane.

scholarly journals Silenced lncRNA SNHG14 restrains the biological behaviors of bladder cancer cells via regulating microRNA-211-3p/ESM1 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Feng ◽  
Zhongxing Li ◽  
Xing Wang ◽  
Guangcheng Ge ◽  
Yuejun Jia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Colony Formation ◽  
Biological Characteristics ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Normal Bladder ◽  
Signaling Axis

Abstract Background Bladder cancer (BCa) is a malignant tumor that occurs on the mucosa of the bladder, in which dysregulated long non-coding RNAs (lncRNAs) are involved. This study investigated the effect of lncRNA small nucleolar RNA host gene 1 (SNHG14) on the biological characteristics of BCa cells from microRNA (miR)-211-3p/ESM1 signaling axis. Methods BCa tissues and the matched normal tissues were collected to test SNHG14, miR-211-3p and ESM1 levels. SNHG14, miR-211-3p and ESM1 levels in BCa cell lines (T24, 5637, UMUC-3 and EJ) and normal bladder epithelial cells SV-HVC-1 were detected for screening the cell lines for follow-up experiments. T24 and UMUC-3 cells were transfected with different plasmids of SNHG14, miR-211-3p or ESM1 to observe the biological characteristics of BCa cells by MTT, colony formation, Transwell assays and flow cytometry. Tumor xenograft was implemented to inspect tumor growth in vivo. The targeting relationships of SNHG14, miR-211-3p and ESM1 were verified by bioinformatics software, RNA pull down assay and luciferase reporter assay. Results Enhanced SNHG14, ESM1 and suppressed miR-211-3p were found in BCa tissues and cells. SNHG14 up-regulated ESM1 via competitive binding with miR-211-3p. Decreased SNHG14 or up-regulated miR-211-3p depressed cell cycle entry, colony formation, invasion, migration and proliferation abilities, and facilitated apoptosis of BCa cells. Decreased SNHG14 or up-regulated miR-211-3p reduced the tumor volume and weight of nude mice with BCa, as well as promoted apoptosis and restrained proliferation of tumor cells. miR-211-3p inhibition or ESM1 overexpression reversed the effects of down-regulation of SNHG14 on BCa, and miR-211-3p up-regulation or ESM1 downregulation reversed the effect of SNHG14 overexpression on BCa. SNHG14 targeted miR-211-3p to regulate ESM1 expression. Conclusion Our study highlights that silenced SNHG14 or elevated miR-211-3p represses the tumorigenic ability of BCa cells, which may be linked to ESM1 knockdown.

scholarly journals l -Tryptophan–Induced Vasodilation Is Enhanced in Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 184-194 ◽  
Author(s):  
Michelle Broekhuizen ◽  
Theo Klein ◽  
Emilie Hitzerd ◽  
Yolanda B. de Rijke ◽  
Sam Schoenmakers ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ex Vivo ◽  
Ultra Performance Liquid Chromatography ◽  
Interferon Γ ◽  
Kynurenine Pathway ◽  
Maternal Circulation ◽  
Placental Perfusion ◽  
Ido1 Expression ◽  
Tryptophan Uptake

l -tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1–dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l -tryptophan–induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l -tryptophan uptake, evidenced by increased l -tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l -tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l -tryptophan in the maternal circulation, suggesting that l -tryptophan metabolites act intracellularly. Maternally applied l -tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l -tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l -tryptophan–induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT ( l -type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l -tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l -tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l -tryptophan uptake rather than IDO1 expression. Increased l -tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.

scholarly journals Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review

2019 ◽  
Vol 22 (4) ◽  
pp. 805-819 ◽  
Author(s):  
Flóra John ◽  
Otto Muzik ◽  
Sandeep Mittal ◽  
Csaba Juhász
Keyword(s):  
Systematic Review ◽  
Pet Radiotracers ◽  
Uptake And Metabolism ◽  
Tryptophan Uptake

Isolation and preliminary characterization of ACNUresistant sublines of rat brain tumors in vivo

1992 ◽  
Vol 77 (3) ◽  
pp. 451-456 ◽  
Author(s):  
T. Ken Yoshida ◽  
Keiji Shimizu ◽  
Athanasios Koulousakis ◽  
Volker Sturm ◽  
Emile Beuls
Keyword(s):  
Brain Tumors ◽  
Rat Brain ◽  
Cell Lines ◽  
Resistant Cell ◽  
Chemotherapeutic Agents ◽  
Cross Resistance ◽  
Chemical Structures ◽  
Wide Range

✓ Two variant cells lines resistant to the nitrosourea derivative ACNU ((1-4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), namely C6/ACNU and 9L/ACNU, were selected in vivo from rat brain tumors. Stable resistance to ACNU proved to be a characteristic of these cell lines, whether they were grown in vivo or in vitro. These cell lines exhibited a different pattern of cross-resistance to a wide range of chemotherapeutic agents with dissimilar chemical structures and mechanisms of action as compared with that of other ACNU-resistant cell lines established in vitro. Distinct cross-resistance was observed in both the C6/ACNU and 9L/ACNU cell lines to chloroethyl-nitrosoureas such as BCNU (carmustine), CCNU (lomustine), and methyl CCNU and, additionally, to vincristine, vinblastine, Adriamycin (doxorubicin), and arabinosylcytosine, but not to bleomycin, methotrexate, c/s-platinum, and 5-fluorouracil. This might point to a multifactorial mechanism of drug resistance in ACNU-resistant cell lines derived from rat C6 and 9L brain tumor cells.

scholarly journals MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

2019 ◽  
Vol 33 (17-18) ◽  
pp. 1236-1251 ◽  
Author(s):  
Niranjan Venkateswaran ◽  
M. Carmen Lafita-Navarro ◽  
Yi-Heng Hao ◽  
Jessica A. Kilgore ◽  
Lizbeth Perez-Castro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Kynurenine Pathway ◽  
Uptake And Metabolism ◽  
Tryptophan Uptake

scholarly journals RTH-149 Cell Line, a Useful Tool to Decipher Molecular Mechanisms Related to Fish Nutrition

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1754
Author(s):  
Guillaume Morin ◽  
Karine Pinel ◽  
Karine Dias ◽  
Iban Seiliez ◽  
Florian Beaumatin
Keyword(s):  
Amino Acid ◽  
Cell Line ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Fish Nutrition ◽  
Multiple Strategies ◽  
First Time ◽  
Interesting Alternative

Nowadays, aquaculture provides more than 50% of fish consumed worldwide but faces new issues that challenge its sustainability. One of them relies on the replacement of fish meal (FM) in aquaculture feeds by other protein sources without deeply affecting the whole organism’s homeostasis. Multiple strategies have already been tested using in vivo approaches, but they hardly managed to cope with the multifactorial problems related to the complexities of fish biology together with new feed formulations. In this context, rainbow trout (RT) is particularly concerned by these problems, since, as a carnivorous fish, dietary proteins provide the amino acids required to supply most of its energetic metabolism. Surprisingly, we noticed that in vitro approaches considering RT cell lines as models to study RT amino acid metabolism were never previously used. Therefore, we decided to investigate if, and how, three major pathways described, in other species, to be regulated by amino acid and to control cellular homeostasis were functional in a RT cell line called RTH-149—namely, the mechanistic Target Of Rapamycin (mTOR), autophagy and the general control nonderepressible 2 (GCN2) pathways. Our results not only demonstrated that these three pathways were functional in RTH-149 cells, but they also highlighted some RT specificities with respect to the time response, amino acid dependencies and the activation levels of their downstream targets. Altogether, this article demonstrated, for the first time, that RT cell lines could represent an interesting alternative of in vivo experimentations for the study of fish nutrition-related questions.

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