Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1

Kamo, Shunsuke; Nakanishi, Takeo; Aotani, Rika; Nakamura, Yoshinobu; Gose, Tomoka; Tamai, Ikumi

doi:10.1016/j.xphs.2017.04.046

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…Blocking SLCO2A1 has been shown to reduce colon cancer tumorigenesis 53 . Importantly, SLCO2A1 can be potently and selectively inhibited by the FDA approved drug suramin 54 . Therefore, SLCO2A1 may be an attractive target in prostate cancer.…”

Section: Resultsmentioning

confidence: 99%

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Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

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Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genomescale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignantcell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.Cancer cells reprogram their metabolism to fulfill the energetic and biosynthetic needs of proliferation, invasion and migration 1 . This is exemplified in prostate cancer, the second most common cancer in American men after melanoma 2 . Previous studies have uncovered profound metabolic dysregulation in multiple pathways, particularly in fatty acid and lipid metabolism 3,4 . Discovering novel cancer-specific metabolic aberrations has significant translational applications, because cancer-associated metabolic dysfunctions can be exploited to advance cancer detection (e.g., 18 F-FDG (Fludeoxyglucose) imaging based on elevated glycolysis in cancer 5 ) and treatment (e.g., L-asparaginase in treating acute lymphoblastic leukemia 6 ).Cancer metabolic reprograming is profoundly impacted by spatial heterogeneity, a fundamental feature of the tumor microenvironment (TME) 7 . Heterogeneous distributions of blood vessels and stromal tissues create uneven spatial gradients of nutrients and metabolic byproducts, which significantly shape the phenotypes of many cell types in the TME 8 . Recent technologies, such as spatial transcriptomics 9,10 and Slide-seq 11 have enabled transcriptomic profiling of hundreds of locations within tissue sections with high spatial resolution (2-100 μm), and have been used to study multiple types of malignancies, including prostate cancer, breast cancer, pancreatic cancer, and melanoma 9,10,12-14 . These spatially-resolved datasets provide novel opportunities to dissect spatial metabolic heterogeneity i...

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Section: Resultsmentioning

confidence: 99%

“…4A), which may influence the sensitivity to immunotherapy. Elevated prostaglandin synthesis may be targeted by suramin, a FDA-approved drug that potently and inhibits the prostaglandin transporter SLCO2A1 54 .…”

Section: Discussionmentioning

confidence: 99%

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

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“…In the in vitro diffusion chamber method, mucosal permeability was evaluated using 6‐carboxyfluorescein, a paracellular marker (Khafagy et al, ; Li et al, ), and the tight junction function was checked from the membrane resistance value obtained by electrophysiological analysis. Although 6‐carboxyfluorescein was used as a paracellular marker, 6‐carboxyfluorescein and its analogs may be used as substrates for the other organic anion transporting polypeptide (OATP) 2A1 and multidrug resistance‐associated protein (MRP) (Bachmeier, Trickler, & Miller, ; Kamo et al, ). In this experiment, permeability was examined in both directions, absorption and excretion, and no difference was observed in either.…”

Section: Discussionmentioning

confidence: 99%

Increased membrane permeation and blood concentration of 6‐carboxyfluorescein associated with dysfunction of paracellular route barrier in the small intestine of ulcerative colitis model rats

Kumagai

Ishii

Morimoto

et al. 2020

Biopharm & Drug Disp

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In the colon of patients with ulcerative colitis (UC), decreased function of the paracellular barrier, especially hypofunction of the tight junction, is associated with pathological conditions. However, there has been no report to date on the function of tight junctions in the small intestine. Here, we focused on the barrier function of the small intestine, especially in tight junctions, and compared it with that of the colon. Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in rats in order to evaluate the function of the paracellular barrier in the jejunum, ileum, and colon. An in vitro diffusion chamber method was used to evaluate membrane resistance, which is an index of tight junction function and mucosal permeability, using 6-carboxyfluorescein (6-CF), a paracellular marker. In the jejunum and colon, with decrease of membrane resistance in the DSS group, mucosal permeability increased, whereas no marked difference was observed in the ileum. In the in situ closed-loop method, absorption of 6-CF from the jejunum was higher than that from the ileum.Immunohistochemical staining of claudin-4 showed heterogeneous attenuation of claudin-4 in the jejunum. Pharmacokinetic parameters were calculated from the blood concentration after intravenous injection and oral administration of 6-CF. In the DSS group, there was a delay in the elimination phase, suggesting a decrease in renal function, and an increase in maximum blood concentration, associated with an increased absorption rate constant. The increased absorption and decreased renal function due to decreased paracellular barrier function in the small intestine and colon may cause fluctuations in drug efficacy and side effects. K E Y W O R D S membrane resistance, paracellular route, small intestine, tight junction, ulcerative colitis

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“…SLCO2A1 has been identified in the pig heart (Van Poucke et al, 2009). Kamo et al (2017) examined the effects of 636 Food and Drug Administration-approved drugs on OATP2A1 transport activity using human embryonic kidney cells (HEK293) cells expressing OATP2A1. The activity of OATP2A1 was strongly inhibited by 51 approved drugs and stimulated by 10.…”

Section: Transportersmentioning

confidence: 99%

“…References Tamai et al, 2000;Fujiwara et al, 2001Lu et al, 1996Kamo et al, 2017Grube et al, 2006Roth et al, 2012Huber et al, 2007 Atilano-Roque and Joy, 2017 Yabuuchi et al, 1999;Okabe et al, 2008;Nakamura et al, 2010Ganapathy et al, 2000Srinivas et al, 2007Zwart et al, 2001 N/A, not available.…”

Section: Transportersmentioning

confidence: 99%

Overview of the Components of Cardiac Metabolism

2019

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Metabolism in organs other than the liver and kidneys may play a significant role in how a specific organ responds to chemicals. The heart has metabolic capability for energy production and homeostasis. This homeostatic machinery can also process xenobiotics. Cardiac metabolism includes the expression of numerous organic anion transporters, organic cation transporters, organic carnitine (zwitterion) transporters, and ATP-binding cassette transporters. Expression and distribution of the transporters within the heart may vary, depending on the patient's age, disease, endocrine status, and various other factors. Several cytochrome P450 (P450) enzyme classes have been identified within the heart. The P450 hydroxylases and epoxygenases within the heart produce hydroxyeicosatetraneoic acids and epoxyeicosatrienoic acids, metabolites of arachidonic acid, which are critical in regulating homeostatic processes of the heart. The susceptibility of the cardiac P450 system to induction and inhibition from exogenous materials is an area of expanding knowledge, as are the metabolic processes of glucuronidation and sulfation in the heart. The susceptibility of various transcription factors and signaling pathways of the heart to disruption by xenobiotics is not fully characterized but is an area with implications for disruption of normal postnatal development, as well as modulation of adult cardiac health. There are knowledge gaps in the timelines of physiologic maturation and deterioration of cardiac metabolism. Cross-species characterization of cardiac-specific metabolism is needed for nonclinical work of optimum translational value to predict possible adverse effects, identify sensitive developmental windows for the design and conduct of informative nonclinical and clinical studies, and explore the possibilities of organ-specific therapeutics.

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Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1

Cited by 19 publications

References 36 publications

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Increased membrane permeation and blood concentration of 6‐carboxyfluorescein associated with dysfunction of paracellular route barrier in the small intestine of ulcerative colitis model rats

Overview of the Components of Cardiac Metabolism

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