Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Kang, Moon Gi; Chung, In Kwon

doi:10.1124/mol.61.4.879

Cited by 41 publications

(29 citation statements)

References 29 publications

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“…Several earlier reports have coupled decreased topo IIα expression with acquired etoposide resistance (40)(41)(42)(43). Conversely, overexpression of topo IIα in etoposide-resistant brain tumor cells restored drug sensitivity (44), illustrating the relationship between topo IIα levels and etoposide cytotoxicity in cancer.…”

Section: Discussionmentioning

confidence: 85%

Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1

Sullivan

Graham

2009

Molecular Cancer Therapeutics

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Intratumoral hypoxia is associated with resistance to therapy in many human cancers, and preexposure of tumor cells to hypoxia confers multidrug resistance. Whereas most anticancer drugs kill proliferating tumor cells by causing DNA damage, a role for hypoxia in the prevention and/or repair of drug-induced DNA damage has not been clear. Using the alkaline comet assay, we provide direct evidence that hypoxia-induced resistance to etoposide in human tumor cells (MDA-MB-231 breast carcinoma and DU-145 prostatic adenocarcinoma) is mainly due to prevention of drug-induced DNA damage (i.e., strand breaks) and that the amount of DNA damage present immediately after etoposide exposure is a good independent predictor of clonogenic survival. Our results also revealed that preexposure to hypoxia did not affect the apparent DNA repair capacity of cells. These findings indicate that the extent of DNA damage resulting from etoposide exposure is a more important determinant of survival than subsequent events after DNA damage. Furthermore, immunofluorescence analysis showed that, in a subpopulation of cells, preexposure to hypoxia decreased the levels of topoisomerase IIα, an enzyme that generates DNA strand breaks when poisoned with etoposide. Treatment of cells with small interfering RNA targeting hypoxia-inducible factor 1 prevented the hypoxia-induced decreases in topoisomerase IIα levels, abolished the protective effect of hypoxia against etoposide-induced DNA damage, and inhibited hypoxia-induced etoposide resistance. These findings support a model of hypoxia-induced drug resistance in which etoposide-induced DNA damage is prevented by HIF-1-dependent adaptations to hypoxia.

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Section: Discussionmentioning

confidence: 85%

Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1

Sullivan

Graham

2009

Molecular Cancer Therapeutics

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“…Control cells were treated with corresponding dimethyl sulfoxide concentrations. Cell growth inhibition was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay (Kang and Chung, 2002).…”

Section: Methodsmentioning

confidence: 99%

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Kim¹,

Kim²,

Lee³

et al. 2003

Mol Pharmacol

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Telomerase activity is expressed in most types of cancer cells but not in normal somatic cells, suggesting that telomerase may be an important target for cancer chemotherapy. Inhibition of telomerase results in telomere erosion, leading to the subsequent growth arrest of cancer cells followed by senescence or cell death. In this study, we screened a chemical library for the inhibition of human telomerase, identifying three inhibitors. All compounds contained a common nitrostyrene moiety conjugated to different side chains. One of these compounds, 3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS), showed the most potent inhibitory effect, with 50% inhibition at ϳ0.4 M and did not inhibit DNA and RNA polymerases, including retroviral reverse transcriptase. A series of enzyme kinetic experiments suggests that DPNS is a mixed-type noncompetitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate primer and the deoxynucleoside-5Ј-triphosphates. Extensive propagation of cancer cell line in the presence of DPNS resulted in progressive telomere erosion followed by the induction of senescence phenotype. The results presented here demonstrate that DPNS is a highly selective, small-molecule telomerase inhibitor in vitro and could be useful as a lead molecule for the further development of inhibitors with an improved potential for efficacy in vivo.

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“…How berberine mediates these effects is not fully understood, but its ability to modulate Mcl-1 (6), Bcl-xL (5), cyclooxygenase (COX)-2 (6), MDR (14), tumor necrosis factor (TNF)-a and IL-6 (15), iNOS (16), , intercellular adhesion molecule-1 and ELAM-1 expression (12), MCP-1 and CINC-1 (18), cyclin D1 (19), activator protein (AP-1; ref. 20), HIF-1a (21), PPAR-g (22), and topoisomerase II (23) has been shown. By using yeast mutants, berberine was found to bind and inhibit stress-induced mitogen-activated protein kinase kinase activation (17).…”

Section: Introductionmentioning

confidence: 99%

Berberine Modifies Cysteine 179 of IκBα Kinase, Suppresses Nuclear Factor-κB–Regulated Antiapoptotic Gene Products, and Potentiates Apoptosis

et al. 2008

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Berberine, an isoquinoline alkaloid derived from a plant used traditionally in Chinese and Ayurvedic medicine, has been reported to exhibit chemopreventive and anti-inflammatory activities through unknown mechanism. Because of the critical role of the transcription factor nuclear factor-KB (NF-KB) in these processes, we investigated the effect of berberine on this pathway. We found that berberine suppressed NF-KB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-KB activation found in certain tumor cells. Suppression of NF-KB activation occurred through the inhibition of phosphorylation and degradation of IKBA by the inhibition of IKB kinase (IKK) activation, leading to suppression of phosphorylation and nuclear translocation of p65, and finally to inhibition of NF-KB reporter activity. Inhibition of IKK by berbeine was direct and could be reversed by reducing agents. Site-specific mutagenesis suggested the involvement of cysteine residue 179 in IKK.

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Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Cited by 41 publications

References 29 publications

Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1

Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Berberine Modifies Cysteine 179 of IκBα Kinase, Suppresses Nuclear Factor-κB–Regulated Antiapoptotic Gene Products, and Potentiates Apoptosis

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