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Dual-channel fluorescence diagnosis of cancer cells/tissues assisted by OATP transporters and cysteine/glutathione.

ABSTRACT: Although fluorescence imaging diagnosis of the differences between cancer cells and normal cells by targeting ligand-based fluorescent probes is useful for recommending personalized therapy to patients, using the differences to diagnose a wide range of cancers is often not possible due to the genetic or phenotypic heterogeneity of cancer cells. In this work a 2-(diphenylphosphino)phenol-functionalized pyronin POP was presented as a dual-channel fluorescence agent for diagnosing a wide range of cancer cell types. The agent could efficiently penetrate cancer cell, rather than normal cell, membranes by active transport of the organic-anion transporting polypeptide (OATP) transporters overexpressed in many types of cancer cell, and is then activated by intracellular cysteine (Cys) and glutathione (GSH) to produce green-emission aminopyronin NP and red-emission thiopyronin SP, thereby enabling its use in dual-channel fluorescence diagnosis of a wide range of cancer cells with excellent contrast. Crucially, POP also displays the ability of dual-channel fluorescence diagnosis of cancer tissues from tumour xenograft models of mice and harvested surgical specimens of patients, thus holding great potential for clinical applications.

SUBMITTER: Zhang H

PROVIDER: S-EPMC5916224 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Dual-channel fluorescence diagnosis of cancer cells/tissues assisted by OATP transporters and cysteine/glutathione.

Zhang Hongxing H Liu Jing J Hu Bo B Wang Linfang L Yang Zhen Z Han Xu X Wang Juanjuan J Bai Wei W Guo Wei W

Chemical science 20180216 12

Although fluorescence imaging diagnosis of the differences between cancer cells and normal cells by targeting ligand-based fluorescent probes is useful for recommending personalized therapy to patients, using the differences to diagnose a wide range of cancers is often not possible due to the genetic or phenotypic heterogeneity of cancer cells. In this work a 2-(diphenylphosphino)phenol-functionalized pyronin <b>POP</b> was presented as a dual-channel fluorescence agent for diagnosing a wide ran ...[more]

PMID: 29732104

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Project description:BackgroundEpidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated.MethodsWe sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1-, 2B1- or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intratumor accumulation of administered steroids by mass spectrometry.ResultsOATP1B1- and 2B-expressing xenografts each showed a threefold increase in tritiated-DHEAS uptake vs vector controls (P=0.002 and P=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15 μg dl-1), OATP1B1- and 2B1-expressing xenografts showed a 3.9-fold (P=0.057) and 1.9-fold (P=0.048) increase in tumor accumulation of DHEAS and a 1.6-fold (P=0.057) and 2.7-fold (P=0.095) increase in DHEA, respectively. At the substantial circulating testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected.ConclusionsOATP transporters measurably alter DHEAS uptake and intratumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.

Dataset Information

Dual-channel fluorescence diagnosis of cancer cells/tissues assisted by OATP transporters and cysteine/glutathione.

Publications

Dual-channel fluorescence diagnosis of cancer cells/tissues assisted by OATP transporters and cysteine/glutathione.

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