Dataset Information

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21.

ABSTRACT: In order to tackle the issue of systemic toxicity in chemotherapy, there is a need to develop novel mechanisms for the activation of protein inhibitors using biomarkers overexpressed in cancer cells. Many current strategies focus on using cancer associated enzymes as a triggering agent for prodrugs. Herein, we detail an alternative approach that harnesses a microRNA (miR-21) that is overexpressed in cancers as the trigger that activates an inhibitor of human carbonic anhydrase-II (hCA-II). Specifically, we have developed a DNA-small molecule chimera (DC) composed of an hCA-II binding lithocholic acid amide (LAA) headgroup that can transition from a rigid duplex state (that does not bind appreciably to hCA) to a single-stranded conformation via a miR-21 trigger. The activated single-stranded DC can project the LAA headgroup into the hCA-II active site and is a robust hCA-II inhibitor (K(i) of 3.12 ?M). This work may spur research into developing new classes of cancer selective protein inhibitors.

SUBMITTER: Chu X

PROVIDER: S-EPMC4709253 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21.

Chu Xiaozhu X Battle Cooper H CH Zhang Nan N Aryal Gyan H GH Mottamal Madhusoodanan M Jayawickramarajah Janarthanan J

Bioconjugate chemistry 20150731 8

In order to tackle the issue of systemic toxicity in chemotherapy, there is a need to develop novel mechanisms for the activation of protein inhibitors using biomarkers overexpressed in cancer cells. Many current strategies focus on using cancer associated enzymes as a triggering agent for prodrugs. Herein, we detail an alternative approach that harnesses a microRNA (miR-21) that is overexpressed in cancers as the trigger that activates an inhibitor of human carbonic anhydrase-II (hCA-II). Speci ...[more]

PMID: 26191606

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Project description:Carbonic anhydrase IX (CA IX) is a transmembrane enzyme that is present in many types of solid tumors. Expression of CA IX is driven predominantly by the hypoxia-inducible factor (HIF) pathway and helps to maintain intracellular pH homeostasis under hypoxic conditions, resulting in acidification of the tumor microenvironment. Carnosine (?-alanyl-L-histidine) is an anti-tumorigenic agent that inhibits the proliferation of cancer cells. In this study, we investigated the role of CA IX in carnosine-mediated antitumor activity and whether the underlying mechanism involves transcriptional and translational modulation of HIF-1? and CA IX and/or altered CA IX function.The effect of carnosine was studied using two-dimensional cell monolayers of several cell lines with endogenous CA IX expression as well as Madin Darby canine kidney transfectants, three-dimensional HeLa spheroids, and an in vivo model of HeLa xenografts in nude mice. mRNA and protein expression and protein localization were analyzed by real-time PCR, western blot analysis, and immunofluorescence staining, respectively. Cell viability was measured by a flow cytometric assay. Expression of HIF-1? and CA IX in tumors was assessed by immunohistochemical staining. Real-time measurement of pH was performed using a sensor dish reader. Binding of CA IX to specific antibodies and metabolon partners was investigated by competitive ELISA and proximity ligation assays, respectively.Carnosine increased the expression levels of HIF-1? and HIF targets and increased the extracellular pH, suggesting an inhibitory effect on CA IX-mediated acidosis. Moreover, carnosine significantly inhibited the growth of three-dimensional spheroids and tumor xenografts compared with untreated controls. Competitive ELISA showed that carnosine disrupted binding between CA IX and antibodies specific for its catalytic domain. This finding was supported by reduced formation of the functional metabolon of CA IX and anion exchanger 2 in the presence of carnosine.Our results indicate that interaction of carnosine with CA IX leads to conformational changes of CA IX and impaired formation of its metabolon, which in turn disrupts CA IX function. These findings suggest that carnosine could be a promising anticancer drug through its ability to attenuate the activity of CA IX.

Dataset Information

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21.

Publications

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21.

Similar Datasets

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