Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Buyse, Chloé; Joudiou, Nicolas; Corbet, Cyril; Feron, Olivier; Mignion, Lionel; Flament, Julien; Gallez, Bernard

doi:10.3390/cancers13174278

Cited by 14 publications

(16 citation statements)

References 58 publications

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“…Furthermore, the CEST-pH approach was able to detect changes in tumor pHe in a mammary tumor model (4T1) following treatment with a mitochondrial pyruvate carrier (MPC) inhibitor (UK-5099), where 31 P NMR spectroscopy did not detect any significant changes. In particular, analysis of histograms of distributions of pHe values revealed that a small part of the tumors was affected by extracellular acidification [46]. In addition to response studies, improvements in imaging acquisitions and volume coverage were achieved with multislice CEST acquisitions allowing a more comprehensive and extensive visualization of tumor extracellular pH [47][48][49][50].…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Jardim‐Perassi

Irrera

Lau

et al. 2023

Contrast Media & Molecular Imaging

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The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups ( p = 0.16 ). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration ( p < 0.001 ). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.

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Section: Discussionmentioning

confidence: 99%

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Jardim‐Perassi

Irrera

Lau

et al. 2023

Contrast Media & Molecular Imaging

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“…As the effects of syrosingopine on tumor cell proliferation were more pronounced on MDA-MB-231 cells than on FaDu cells, in vivo studies were carried out on the MDA-MB-231 tumor model to measure potential changes in pHe and in tumor growth. CEST-MRI was applied using a protocol adapted from our previous work on mitochondrial pyruvate carrier (MPC) inhibition [24]. The administration pattern of syrosingopine was inspired by the work of Benjamin et al [17,18].…”

Section: In Vivo Phe Measurements With Cest-mrimentioning

confidence: 99%

“…CEST Calibration In Vitro All experiments were performed on an 11.7T Biospec MRI (Bruker, Ettlingen, Germany). Calibration studies were performed as previously described [24]. CEST acquisitions were acquired with a 1 H volume coil with a 40 mm inner diameter.…”

Section: Tumor Modelmentioning

confidence: 99%

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Evaluation of Syrosingopine, an MCT Inhibitor, as Potential Modulator of Tumor Metabolism and Extracellular Acidification

et al. 2022

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Extracellular acidification has been shown to be an important characteristic of invasive tumors, as it promotes invasion and migration but also resistance to treatments. Targeting transporters involved in the regulation of tumor pH constitutes a promising anti-tumor approach, as it would disrupt cellular pH homeostasis and negatively impact tumor growth. In this study, we evaluated the impact of syrosingopine, an inhibitor of MCT1 and MCT4, as a modulator of tumor metabolism and extracellular acidification in human breast cancer (MDA-MB-231) and pharyngeal squamous cell carcinoma (FaDu) cell models. In both models in vitro, we observed that exposure to syrosingopine led to a decrease in the extracellular acidification rate, intracellular pH, glucose consumption, lactate secretion and tumor cell proliferation with an increase in the number of late apoptotic/necrotic cells. However, in vivo experiments using the MDA-MB-231 model treated with a daily injection of syrosingopine did not reveal any significant change in extracellular pH (pHe) (as measured using CEST-MRI) or primary tumor growth. Overall, our study suggests that targeting MCT could lead to profound changes in tumor cell metabolism and proliferation, and it warrants further research to identify candidates without off-target effects.

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“…It could inhibit the mitochondrial acetone carrier (MPC) by binding to C54 of MPC2 in a covalent reversible manner with a low dissociation rate of the inhibitor-carrier complex, which assists the transport of pyruvate across the inner mitochondrial membrane, plays a key role in the metabolism of carbohydrates, lipids and amino acids, and then blocks the entry of pyruvate into mitochondria, weakening mitochondrial oxidative phosphorylation (OXPHOS) and triggering aerobic glycolysis [ 1 , 3 – 5 ]. Compared with parental cells, UK-5099-treated tumor cells also showed stronger invasive ability [ 6 ], and a significant decrease in tumor pHe of 0.22 units in UK-5099 treated mice [ 7 ]. Moreover, UK-5099 inhibited the oxidation of pyruvate in rat heart mitochondria in a nonlinear inhibitory kinetic manner [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Determination and pharmacokinetics study of UK-5099 in mouse plasma by LC–MS/MS

Zeng

et al. 2022

BMC Vet Res

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Background UK-5099 is a potent mitochondrial acetone carrier inhibitor, that exhibits anticancer activity. Recently, the anti-Toxoplasma gondii activity of UK-5099 was proposed, and in vivo studies of its pharmacokinetics in BALB/c mice are necessary to further evaluate the clinical effect of UK-5099. Methods and results A simple and fast high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) analysis method was established and verified in terms of its linearity, matrix effect, accuracy, precision, recovery and stability. The analytes were separated by an Agilent ZORBAX XDB-C18 column (2.1 × 50 mm, 3.5 μm) at 30 °C. A gradient mobile phase consisting of water with 0.1% formic acid (FA) (phase A) and acetonitrile (ACN) (phase B) was delivered at a flow rate of 0.40 mL·min−1 with an injection volume of 5 μL. A good linear response was obtained in a concentration range of 5–5000 ng·mL−1 (r2 = 0.9947). The lower limit of quantification (LLOQ) was 5 ng·mL−1. The extraction recovery of UK-5099 was greater than 95%. The inter- and intra-day accuracy and precision of the method showed relative standard deviations (RSDs) of less than 15%. This method has been successfully applied to the pharmacokinetic evaluation of UK-5099 in mouse plasma. In health mice, the main pharmacokinetic parameters of UK-5099 after intraperitoneal administration were measured using a noncompartmental model, in which the AUC0-t was 42,103 ± 12,072 ng·h·mL−1 and the MRT0-t was 0.857 ± 0.143 h. The peak concentration (Cmax) was 82,500 ± 20,745 ng·h·mL−1, which occurred at a peak time (Tmax) = 0.250 ± 0.000 h. Conclusions A fast and sensitive HPLC–MS/MS method was developed, validated and successfully used for the determination of UK-5099 levels in mice after intraperitoneal administration. This study was the first report of the pharmacokinetic parameters of UK-5099 in mice, which will help to further study the administration of UK-5099 in animals and humans.

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Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

Cited by 14 publications

References 58 publications

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Evaluation of Syrosingopine, an MCT Inhibitor, as Potential Modulator of Tumor Metabolism and Extracellular Acidification

Determination and pharmacokinetics study of UK-5099 in mouse plasma by LC–MS/MS

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