ATP-Binding Cassette Transporters Modulate Both Coelenterazine- and D-Luciferin-Based Bioluminescence Imaging

Huang, Ruimin; Vider, Jelena; Serganova, Inna; Blasberg, Ronald G.

doi:10.2310/7290.2010.00045

Cited by 18 publications

(18 citation statements)

References 47 publications

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“…Transport of luciferase substrates across the cell membrane does affect BLI readout intensity from intact cells. In-vitro and in-vivo data indicate that ABCG2 only affects BLI signal intensity generated from D-luciferin [31].…”

Section: Discussionmentioning

confidence: 96%

Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells

Sun

Gu²,

Zhu³

et al. 2016

Anti-Cancer Drugs

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A lack of methods capable of exploring real-time intracellular drug deposition has since limited the investigation of gemcitabine-induced multidrug resistance in vitro and in vivo. Specifically, resistance induced by D-luciferin, a substrate of the breast cancer resistance protein (ABCG2/BCRP), has recently attracted clinical attention, but further investigation has been limited. Herein, the intracellular pharmacokinetic behavior of D-luciferin was investigated in pancreatic cancer cell lines in real time by using bioluminescence imaging. To achieve this feat, BxPC3 and Panc1 pancreatic cancer cells overexpressing firefly luciferase were treated with gemcitabine in a dose and time gradient manner in vitro. The intracellular pharmacokinetic profiles of each group were then determined through the acquisition of bioluminescent signal intensity of D-luciferin in cells. Simultaneously, key pharmacokinetic parameters including area under the curve, elimination rate constant (K), and mean resident time were calculated according to the noncompartment model. ABCG2 protein levels following gemcitabine treatment were detected through western blot, and gemcitabine showed no significant effect on luciferase activity over dimethyl sulfoxide (DMSO) as a control (P>0.05). However, gemcitabine significantly increased K values while suppressing area under the curve and mean resident time compared with DMSO (P<0.05) and increased ABCG2 expression over DMSO-treated cells. In addition, gemcitabine increased the elimination rate of the ABCG2 substrate, D-luciferin, and decreased D-luciferin accumulation in BxPC3 and Panc1 cells in a dose-response manner. Advances made herein illustrate the versatility of the in-vitro bioluminescent model and its capability to observe the onset of chemoresistance in real time.

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Section: Discussionmentioning

confidence: 96%

Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells

Sun

Gu²,

Zhu³

et al. 2016

Anti-Cancer Drugs

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“…Using two distinct luciferase reporter systems, we were able to image the location of Myc-CaP tumors with the Renilla luciferase (Rluc) reporter 54 and image the trafficking of anti-hPSMA CAR T cells with the tdRFP/CBRLuc reporter. First, we assessed the capacity of systemically administered anti-hPSMA CAR T cells to traffic and accumulate within established subcutaneous Myc-CaP:hPSMA(+) tumors.…”

Section: Resultsmentioning

confidence: 99%

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Serganova

Мороз

Cohen

et al. 2017

Molecular Therapy - Oncolytics

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Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb). PDL-1 expression was detected in Myc-CaP murine prostate tumors growing in immune competent FVB/N and immune-deficient SCID mice. Endogenous CD3+ T cells were restricted from the centers of Myc-CaP tumor nodules growing in FVB/N mice. Following anti-programmed cell death protein 1 (PD-1) treatment, the restriction of CD3+ T cells was reversed, and a tumor-treatment response was observed. Adoptive hPSMA-CAR T cell immunotherapy was enhanced when combined with PD-1 blockade, but the treatment response was of comparatively short duration, suggesting other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors. Interestingly, an “inverse pattern” of CAR T cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation. The lower BLI signal intensity in the hPSMA test tumors (compared with controls) is due in part to a decrease in T cell mitochondrial function following T cell activation, which may limit the intensity of the ATP-dependent Luciferin-luciferase bioluminescence signal.

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“…A mouse model for prostate cancer metastasis to lymph nodes was generated by orthotopically implanting PC-3 cells (1 × 10 6 cells in 30 μl 50% matrigel (BD Biosciences) in F-12K medium) stably transduced with a retroviral dual-reporter construct (SFG-click beetle luciferase-IRES-mCherry that was generously provided by Dr. Vladimir Ponomarev) into the left dorsal lobes of the prostates of 8–12 week old C.B-17 severe combined immunodeficiency (SCID, defined flora) male mice ( n = 6; Taconic, Germantown, NY) [27–28][29]. A cohort of non-tumor-bearing mice ( n = 4) was included as a control group for this study.…”

Section: Methodsmentioning

confidence: 99%

Detection of Lymph Node Metastases with SERRS Nanoparticles

et al. 2016

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Purpose The accurate detection of lymph node metastases in prostate cancer patients is important to direct treatment decisions. Our goal was to develop an intra-operative imaging approach to distinguish normal from metastasized lymph nodes. We therefore developed and tested gold-silica surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles that demonstrate high uptake within normal lymphatic tissue, and negligible uptake in areas of metastatic replacement. Procedures We evaluated the ability of SERRS nanoparticles to delineate lymph node metastases in an orthotopic prostate cancer mouse model using PC-3 cells transduced with mCherry fluorescent protein. Tumor bearing mice (n = 6) and non-tumor bearing control animals (n = 4) were injected intravenously with 30 fmol/g SERRS nanoparticles. After 16–18 hours, the retroperitoneal lymph nodes were scanned in situ and ex vivo with a Raman imaging system and a hand-held Raman scanner and data corroborated with fluorescence imaging for mCherry protein expression and histology. Results The SERRS nanoparticles demonstrated avid homing to normal lymph nodes, but not to metastasized lymph nodes. In cases where lymph nodes were partially infiltrated by tumor cells, the SERRS signal correctly identified, with sub-millimeter precision, healthy from metastasized components within the same lymph node. Conclusions This study serves as a first proof-of-principle that SERRS nanoparticles enable high precision and rapid intraoperative discrimination between normal and metastasized lymph nodes.

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ATP-Binding Cassette Transporters Modulate Both Coelenterazine- and D-Luciferin-Based Bioluminescence Imaging

Cited by 18 publications

References 47 publications

Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells

Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells

Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Detection of Lymph Node Metastases with SERRS Nanoparticles

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