The association between chemosensitivity and Pgp, GST-π and Topo II expression in gastric cancer

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Abstract

Background

To investigate the relationship between P-glycoprotein (Pgp), glutathione S-transferase π (GST-π) and topoisomerase II (Topo II) expression and human gastric cancer chemoresistance in vitro.

Methods

Primary single-cell suspensions were prepared from fresh specimens of primary gastric cancer and exposed to hydroxycamptothecin (HCPT), cisplatin (CDDP), 5-fluorouracil (5-FU), adriamycin (ADM) and mitomycin (MMC) for 48 h. Cell metabolic activity and rate of inhibition were evaluated using tetrazolium (MTT) assay. Pgp, GST-π and Topo II expression was determined in gastric carcinoma tissue samples using immunohistochemistry.

Results

Chemosensitivity of the gastric cancer cells varied; the rates of inhibition of cells exposed to HCPT, CDDP and 5-FU were significantly higher than that of cells exposed to ADM and MMC ( p < 0.05). Gastric cancer cells with Pgp expression were resistant to ADM and HCPT ( p = 0.008 and p = 0.011, respectively). Cells resistant to 5-FU, CDDP and MMC had significantly higher GST-π expression ( p < 0.05). Topo II expression was significantly lower in cells resistant to HCPT, ADM and MMC ( p < 0.05). Pgp and GST-π expression may contribute to primary resistance of gastric cancer cells to some chemotherapeutic drugs, while Topo II expression may indicate HCPT, ADM and MMC sensitivity.

Conclusions

Pgp, GST-π and Topo II detection and the MTT assay could be used as predictors in chemotherapeutic drug administration and for identifying drug resistance in gastric carcinoma.

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The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3448329111142964.

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Most cited references 16

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Blood-brain barrier active efflux transporters: ATP-binding cassette gene family.

Wolfgang Löscher, Heidrun Potschka (2004)

The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.

Carmelo R. Tomas (2005)

Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.

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Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer.

Ariena Kersbergen, J Iyer, Sven Rottenberg … (2009)

We have found previously that acquired doxorubicin resistance in a genetically engineered mouse model for BRCA1-related breast cancer was associated with increased expression of the mouse multidrug resistance (Mdr1) genes, which encode the drug efflux transporter ATP-binding cassette B1/P-glycoprotein (P-gp). Here, we show that even moderate increases of Mdr1 expression (as low as 5-fold) are sufficient to cause doxorubicin resistance. These moderately elevated tumor P-gp levels are below those found in some normal tissues, such as the gut. The resistant phenotype could be completely reversed by the third-generation P-gp inhibitor tariquidar, which provides a useful strategy to circumvent this type of acquired doxorubicin resistance. The presence of MDR1A in drug-resistant tumors with a moderate increase in Mdr1a transcripts could be shown with a newly generated chicken antibody against a mouse P-gp peptide. Our data show the usefulness of realistic preclinical models to characterize levels of Mdr1 gene expression that are sufficient to cause resistance.

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Author and article information

Journal

Journal ID (nlm-ta): Diagn Pathol

Journal ID (iso-abbrev): Diagn Pathol

Title: Diagnostic Pathology

Publisher: BioMed Central

ISSN (Electronic): 1746-1596

Publication date Collection: 2013

Publication date (Electronic): 10 December 2013

Volume: 8

Page: 198

Affiliations

[1 ]Department of Pathology, General Hospital of Jinan Military Command, Jinan, China

[2 ]Department of Laboratory Diagnosis, General Hospital of Jinan Military Command, Jinan, China

Article

Publisher ID: 1746-1596-8-198

DOI: 10.1186/1746-1596-8-198

PMC ID: 3901556

PubMed ID: 24326092

SO-VID: 5d0d9f34-7d18-48fa-99dc-991be00e09c8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

The association between chemosensitivity and Pgp, GST-π and Topo II expression in gastric cancer

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Abstract

Background

Methods

Results

Conclusions

Virtual slides

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Karger: Oncology

Most cited references 16

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family.

Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.

Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer.

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