Indomethacin and SC236 enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells via inhibiting P-glycoprotein and MRP1 expression

Ye, Caiguo; Wu, William Ka Kei; Yeung, John H.K.; Li, Haitao; Li, Zhijie; Wong, Corine Sau Man; Ren, Shengxiang; Zhang, Lin; Fung, Kwok‐Pui; Cho, Chi-Hin

doi:10.1016/j.canlet.2011.01.025

Cited by 38 publications

(38 citation statements)

References 21 publications

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“…3A). We and others recently identified the cyclooxygenase inhibitor indomethacin as a drug resistance modulator (16,(27)(28)(29) with suppression of ABCA3 expression on the transcriptional level (16,28,30). Importantly, indomethacin cotreatment almost completely diminished the doxorubicin-induced increase in ABCA3 expression after doxorubicin ( Fig.…”

Section: Trapping Of Anthracyclines In Exosomesmentioning

confidence: 76%

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Koch

Aung

Vogel

et al. 2016

Clinical Cancer Research

106

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Purpose: Although R-CHOP-based immunochemotherapy cures significant proportions of patients with aggressive B-cell lymphoma, tumor cell susceptibility to chemotherapy varies, with mostly fatal outcome in cases of resistant disease. We and others have shown before that export of cytostatic drugs contributes to drug resistance. Now we provide a novel approach to overcome exosome-mediated drug resistance in aggressive B-cell lymphomas.Experimental Design: We used well-established centrifugation protocols to purify exosomes from DLBCL cell lines and detected anthracyclines using FACS and HPLC. We used shRNA knockdown of ABCA3 to determine ABCA3 dependence of chemotherapy susceptibility and monitored ABCA3 expression after indomethacin treatment using qPCR. Finally, we established an in vivo assay using a chorioallantoic membrane (CAM) assay to determine the synergy of anthracycline and indomethacin treatment. Results:We show increased efficacy of the anthracycline doxorubicin and the anthracenedione pixantrone by suppression of exosomal drug resistance with indomethacin. B-cell lymphoma cells in vitro efficiently extruded doxorubicin and pixantrone, in part compacted in exosomes. Exosomal biogenesis was critically dependent on the expression of the ATP-transporter A3 (ABCA3). Genetic or chemical depletion of ABCA3 augmented intracellular retention of both drugs and shifted the subcellular drug accumulation to prolonged nuclear retention. Indomethacin increased the cytostatic efficacy of both drugs against DLBCL cell lines in vitro and in vivo in a CAM assay.Conclusions: We propose pretreatment with indomethacin toward enhanced antitumor efficacy of anthracyclines and anthracenediones. Clin Cancer Res; 22(2); 395-404. Ó2015 AACR.

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Section: Trapping Of Anthracyclines In Exosomesmentioning

confidence: 76%

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Koch

Aung

Vogel

et al. 2016

Clinical Cancer Research

106

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“…Indomethacin and a COX-2 selective inhibitor, SC236, sensitised HepG2 human hepatocellular carcinoma cells to the cytotoxic effects of doxorubicin. This effect was the result of increased intracellular retention and accumulation of doxorubicin via the inhibition of P-gp and MDR associated protein 1 (MRP1) expression and activity (90). Kang et al (91) detected an inhibition of the MRP1 efflux pump and enhanced doxorubicin cytotoxicity with celecoxib treatment.…”

Section: Combination Of Nsaids With Chemotherapeutic Drugs In Vitromentioning

confidence: 99%

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

Hiľovská

Jendželovský

Fedoročko

2014

Molecular and Clinical Oncology

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“…While a large proportion of doxorubicin is eliminated from the body unchanged, the main pathway of doxorubicin metabolism is two-electron reduction by cytosolic reductases, of which carbonyl reductase 1 is the most important in the liver (10). However, doxorubicin resistance in HCC cells is predominantly associated with the expression of adenosine triphosphate-binding cassette (ABC) transporters such as ABCB1 (multi-drug resistance gene; MDR1) or ABCC1 (multidrug resistance-associated protein 1; MRP1) (10,(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

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Indomethacin and SC236 enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells via inhibiting P-glycoprotein and MRP1 expression

Cited by 38 publications

References 21 publications

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

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