Modulation of doxorubicin sensitivity by cyclosporine A in hepatocellular carcinoma cells and their doxorubicin‐resistant sublines

Shiraga, Kunihiro; Sakaguchi, Kohsaku; Senoh, Tomonori; Ohta, Takeyuki; Ogawa, Shin; Sawayama, Tomoyuki; Mouri, Hirokazu; Fujiwara, Akiko; Tsuji, Takao

doi:10.1046/j.1440-1746.2001.02457.x

Cited by 16 publications

(7 citation statements)

References 24 publications

(29 reference statements)

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“…XTT activity was significantly reduced by incubation with 0.125 µM doxorubicin in HepG2 cells (60%; P=0.0075) and Hep3B cells (83%-fold; P=0.0003). The determined toxic dose ranges were comparable to previous in vitro studies using the same HCC cell lines (27)(28)(29)(30)(31)(32). Phase-contrast microscopy confirmed that, after 48 h incubation with a concentration of 1 µM doxorubicin, 10-20% of HCC cells survived (Fig.…”

Section: Selection Of Hcc Cells Surviving Doxorubicin Treatmentsupporting

confidence: 84%

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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Section: Selection Of Hcc Cells Surviving Doxorubicin Treatmentsupporting

confidence: 84%

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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“…Overexpression of MDR1 was observed in many types of cancer such as HCC[42] and non-small-cell lung cancer[43]. In HCC, it was proven that amplification of MDR1 mRNA is probably the main mechanism underlying acquired doxorubicin resistance[44]. The protein encoded by STAT1 is a member of the STAT protein family.…”

Section: Discussionmentioning

confidence: 99%

The Role of Proline Rich Tyrosine Kinase 2 (Pyk2) on Cisplatin Resistance in Hepatocellular Carcinoma

Wang

Sun

et al. 2011

PLoS ONE

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Aims We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism.Methodology/Principal FindingsStable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples.ConclusionsOur results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes.

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“…One method of generating doxorubicin-resistant cultured HCC cells for study is to select for resistant HCC cells in vitro after exposing them to incrementally increasing doses of doxorubicin. This method consistently induces the expression of MDR1 and other ABC family members [31,32], and the upregulation of these transporters can be shown to cause drug resistance since inhibitors of ABC proteins such as verapamil and cyclosporine A are able to restore doxorubicin sensitivity [33]. However, verapamil has not proven to be useful as a doxorubicin sensitizing agent in patients, perhaps due to the presence of other efflux transporters, pharmacological interactions between the drugs [34], the loss of important normal physiological functions [35], or the presence of unrelated resistance mechanisms.…”

Section: Molecular Mechanisms Of Doxorubicin Resistancementioning

confidence: 99%

“…None have yet to demonstrate benefit in clinical trials. In experimental models of HCC, doxorubicin chemosensitization has been achieved with PP2A inhibitors [123], CD13 antibodies [116] or different approaches to inhibit MDR transporters including small molecule inhibitors and antisense constructs [33,124]. Further understanding of the mechanisms responsible for doxorubicin resistance will thus be important to make chemosensitization a routine part of the TACE treatment protocol.…”

Section: Future Perspectivementioning

confidence: 99%

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

2015

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Hepatocellular carcinoma, one of the most common solid tumors worldwide, is poorly responsive to available chemotherapeutic approaches. While systemic chemotherapy is of limited benefit, intra-arterial delivery of doxorubicin to the tumor frequently produces tumor shrinkage. Its utility is limited, in part, by the frequent emergence of doxorubicin resistance. The mechanisms of this resistance include increased expression of multidrug resistance efflux pumps, alterations of the drug target, topoisomerase, and modulation of programmed cell death pathways. Many of these effects result from changes in miRNA expression and are particularly prominent in tumor cells with a stem cell phenotype. This review will summarize the current knowledge on the mechanisms of doxorubicin resistance of hepatocellular carcinoma and the potential for approaches toward therapeutic chemosensitization.

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Modulation of doxorubicin sensitivity by cyclosporine A in hepatocellular carcinoma cells and their doxorubicin‐resistant sublines

Abstract: In HCC, the amplification of MDR1 mRNA is probably the main mechanism underlying acquired DOR resistance. Cyclosporine is also indicated to be highly active in potentiating the anticancer activity of DOR in HCC cells and their DOR-resistant sublines.

Cited by 16 publications

References 24 publications

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

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

The Role of Proline Rich Tyrosine Kinase 2 (Pyk2) on Cisplatin Resistance in Hepatocellular Carcinoma

Mechanisms of doxorubicin resistance in hepatocellular carcinoma

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