Mechanism of Resistance to Oxidative Stress in Doxorubicin Resistant Cells.

Furusawa, Shinobu; Kimura, Eiki; Kisara, Satoko; Nakano, Shinya; Murata, Ryo; Tanaka, Yorihisa; Sakaguchi, Shuhei; Takayanagi, Motowo; Takayanagi, Yoshio; Sasaki, Ken‐ichi

doi:10.1248/bpb.24.474

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…ROS generation and subsequent oxidative damage to the cell membrane is one of the major mechanisms of radiotherapy-mediated apoptotic cell death [28]. Similarly, many chemotherapeutic agents, including cisplatin [29], paclitaxel [30], doxorubicin [31,32], and the histone deacetylase inhibitor suberoylanilide hydroxamic acid, induce ROS generation in target cells [33]. Moreover, scavenging of ROS with antioxidants causes cells to resist apoptosis induced by gamma-irradiation and various chemotherapeutic agents [34].…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in NSC-741909-induced apoptosis of cancer cells

Wei

Guo

et al. 2010

J Transl Med

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BackgroundNSC-741909 is a novel anticancer agent that can effectively suppress the growth of several cell lines derived from lung, colon, breast, ovarian, and kidney cancers. We recently showed that NSC-741909-induced antitumor activity is associated with sustained Jun N-terminal kinase (JNK) activation, resulting from suppression of JNK dephosphorylation associated with decreased protein levels of MAPK phosphatase-1. However, the mechanisms of NSC-741909-induced antitumor activity remain unclear. Because JNK is frequently activated by oxidative stress in cells, we hypothesized that reactive oxygen species (ROS) may be involved in the suppression of JNK dephosphorylation and the cytotoxicity of NSC-741909.MethodsThe generation of ROS was measured by using the cell-permeable nonfluorescent compound H2DCF-DA and flow cytometry analysis. Cell viability was determined by sulforhodamine B assay. Western blot analysis, immunofluorescent staining and flow cytometry assays were used to determine apoptosis and molecular changes induced by NSC-741909.ResultsTreatment with NSC-741909 induced robust ROS generation and marked MAPK phosphatase-1 and -7 clustering in NSC-741909-sensitive, but not resistant cell lines, in a dose- and time-dependent manner. The generation of ROS was detectable as early as 30 min and ROS levels were as high as 6- to 8-fold above basal levels after treatment. Moreover, the NSC-741909-induced ROS generation could be blocked by pretreatment with antioxidants, such as nordihydroguaiaretic acid, aesculetin, baicalein, and caffeic acid, which in turn, inhibited the NSC-741909-induced JNK activation and apoptosis.ConclusionOur results demonstrate that the increased ROS production was associated with NSC-741909-induced antitumor activity and that ROS generation and subsequent JNK activation is one of the primary mechanisms of NSC-741909-mediated antitumor cell activity.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress in NSC-741909-induced apoptosis of cancer cells

Wei

Guo

et al. 2010

J Transl Med

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“…Cisplatin and doxorubicin treatment stimulated ROS production in parental HEp2 cell line, whereas in ␣ v ␤ 3 integrin-expressing cells we observed increased elimination of ROS that could be abrogated by BSO. Similarly, in doxorubicin resistant mouse leukemic cells (P388) reduced effect of oxidative stress was related to an increase in intracellular GSH level (Furusawa et al, 2001).…”

Section: Downloaded Frommentioning

confidence: 92%

“…Similarly, a perturbation of ROS and intracellular GSH levels associated with enhancement of cell death was observed in cisplatinand doxorubicin-sensitive breast cancer MCF-7 cells (Osbild et al, 2006). Reduced effect of oxidative stress in doxorubicinresistant mouse P388/S leukemia cells toward resistant cells may be related to an increase in intracellular GSH level as well (Furusawa et al, 2001). Our conclusion that ␣ v ␤ 3 integrin-expressing HEp2 cells are resistant to several anticancer drugs due to the increased elimination of drug-induced ROS is further supported by the fact that these cells show resistance to the nitric oxide donor sodium nitroprusside dihydrate that acts also through induction of ROS.…”

Section: Downloaded Frommentioning

confidence: 99%

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Brozović

Majhen²,

Roje³

et al. 2008

Molecular Pharmacology

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As a model for determination of the role of integrins in drug resistance, we used ␣ v ␤ 3 integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of ␣ v ␤ 3 integrin expression. The ␣ v ␤ 3 integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-␣ v ␤ 3 integrin-expressing cells, the constitutive expression of Bcl-2 protein and the level of glutathione (GSH) were increased compared with HEp2 cells. Pretreatment of HEp2-␣ v ␤ 3 integrin-expressing cells with an inhibitor of GSH synthesis, buthionine sulfoximine (BSO), decreased the level of GSH and partially reverted drug resistance to all above-mentioned drugs, but it did not influence the expression of Bcl-2. Sensitivity to selected anticancer drugs did not change with overexpression of Bcl-2 in HEp2 cells, nor with silencing of Bcl-2 in HEp2-␣ v ␤ 3 integrin-expressing cells, indicating that Bcl-2 is not involved in resistance mechanism. There was no difference in DNA platination between HEp2 and HEp2-␣ v ␤ 3 integrin-expressing cells, indicating that the mechanism of drug resistance is independent of cisplatin detoxification by GSH. A strong increase of reactive oxidative species (ROS) formation during cisplatin or doxorubicin treatment in HEp2 cells was reduced in HEp2-␣ v ␤ 3 integrin-expressing cells. Since this increased elimination of ROS could be reverted by GSH depletion, we concluded that multidrug resistance is the consequence of GSH-dependent increased ability of ␣ v ␤ 3 -expressing cells to eliminate drug-induced ROS.Chemotherapy often results in the development of drug resistance. Several molecular mechanisms have been recognized as a cause of resistance, such as reduced drug accumulation, increased drug inactivation, increased ability to repair and/or tolerate DNA lesions, and inhibition of apoptosis. Recent findings show that integrin-mediated adhesion to the extracellular matrix can modify cellular response to chemotherapeutic drugs through mechanisms such as inhibition of apoptosis, decreased cellular proliferation, and alterations in a drug target (Damiano, 2002;Ambriović-Ristov and Osmak, 2006). Integrins are cell surface adhesion molecules that connect cells to components of the extracellular matrix. They are assembled from a set of diverse ␣-(18) and ␤-(8) subunits that associate to form 24 differentially composed heterodimers exhibiting specific but also redundant ligand binding and expression patterns. Integrins modulate many signaling pathways, supporting cell survival and proliferation and influencing expression of differentiation-regulated genes (Danen, 2005).The most extensively used model for investigation of molecular mechanisms of drug resistance is the development of resistant cells by selected anticancer drug treatment and then comparing the biological and biochemical characteristics of those cells, allowing for the causes of drug resistance to be determined. Despite increased expression of several integrin subunits and/or he...

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“…Unfortunately, like many other chemotherapeutic agents, the continuous administration of ADR causes drug resistance so that the therapeutic efficacy dramatically declines 5 . Clinical data have confirmed that both chemotherapy sensitivity and patient survival were negatively correlated with P-glycoprotein (P-gp) expression.…”

Section: Introductionmentioning

confidence: 99%

The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells

Cao

Dong

et al. 2017

Sci Rep

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Adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance in breast cancer cells. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and decreased glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expression of P-gp. The present study showed that ADR inhibited the influx of cystine (the source material of GSH) and the activity of the SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that the down-regulation/silence of SLC7A11, or cystine deprivation, or enhanced ROS exposure significantly increased P-gp expression in MCF-7 cells. The down-regulation of SLC7A11 markedly enhanced ROS induced P-gp over-expression and drug resistance in MCF-7 cells; a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and increased ROS dramatically promoted P-gp expression, which could be reversed by N-acetylcysteine. In contrast, the over-expression of SLC7A11, or supplementation with sufficiently cystine, or treatment with N-acetylcysteine significantly decreased P-gp expression and activity. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the expression and function of P-gp, and that SLC7A11 might be a potential target modulating ADR resistance.

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Mechanism of Resistance to Oxidative Stress in Doxorubicin Resistant Cells.

Cited by 17 publications

References 32 publications

Oxidative stress in NSC-741909-induced apoptosis of cancer cells

Oxidative stress in NSC-741909-induced apoptosis of cancer cells

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells

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