Modulation of DNA topoisomerase II activity and expression in melanoma cells with acquired drug resistance

Lage, Hermann; Helmbach, Heike; Dietel, Manfred; Schadendorf, Dirk

doi:10.1054/bjoc.1999.0947

Cited by 55 publications

(49 citation statements)

References 15 publications

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“…An increase of topoisomerase activity in association with resistance to doxorubicin and etoposide in melanoma cells has been reported. 19 Mutant Topo-II has also been correlated with etoposide resistance in a melanoma cell line. 20 Therefore, alteration of topoisomerase activity might be involved in mediating resistance to specific drugs in melanoma.…”

Section: Drug Resistance Mediated By Altered Enzyme Activationmentioning

confidence: 99%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

162

137

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Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/ extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.

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Section: Drug Resistance Mediated By Altered Enzyme Activationmentioning

confidence: 99%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

162

137

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“…To this end, topoisomerase inhibiting agents alone or in combination with other antineoplastics have been found to exert antiproliferative effects against malignant melanocytes [19,20] despite the fact that selective resistance against them may develop in the same cells [21]. Since the expression of individual topoisomerases in melanoma may vary [14] in addition to often aberrant function of p53-dependent pathway which is mostly targeted by topoisomerase inhibitors [2], concerted suppression of topoisomerase I and II in the same cells may be perspective in enhancing cytotoxicity and proapoptic response while overcoming aforementioned obstacles.…”

Section: Discussionmentioning

confidence: 99%

“…Although generally efficient in inducing apoptosis mainly via promoting DNA strand breaks and activating p53-dependent mitochondrial apoptosis, their efficiency even in combination with other cytotoxic drugs in case of advanced melanoma remains very limited. Besides their pharmacology, the main reasons of this failure seem to be the decreased expression and activity of topoisomerases [14], perturbations in p53-mediated response to DNA damage as well the aberrant intrinsic apoptotic pathway signaling [15]. Still, antineoplastic activity of these drugs is rather complex and as suggested by Malignant melanoma belongs to the class of aggressive neoplastic diseases which often metastasize at early stages and show high resistance to chemotherapy.…”

mentioning

confidence: 99%

Dual inhibition of topoisomerases enhances apoptosis in melanoma cells

Rudolf¹,

Červinka²,

Rudolf³

2010

neo

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The cytotoxicity of topoisomerase I inhibiting camptothecin, topoisomerase II inhibiting etoposide and their combination were investigated in wild type p53 Bowes and mutant p53 SK-MEL-28 melanoma cell lines during 24h. A combination of camptothecin and etoposide (1 μg/ml + 10 μg/ml) proved to be efficient in both types of cell lines, although mutant p53 cells exhibited a higher resistance. Further studies proved that in Bowes cells, a combination of drugs induced p53-dependent mitochondrial apoptosis characterized by activation of caspases-8 and -2, -9 and -3 with some concurrent involvement of oxidative stress. In SK-MEL-28 cells, apoptosis was found to be mediated via increased oxidative stress, activation of stress kinases such as p38 and SAPK/JNK and mitochondrial dysfunction without significant involvement of p53 and its transactivated target genes. These results demonstrate efficiency of dual inhibition of topoisomerases in melanoma cells with functional as well as mutant p53 and point out at possible further investigation of this modality in preclinical and clinical oncology.

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“…11,19 In brief, samples of 20 lg nuclear proteins were loaded onto a 6% SDS-PA gel. Separated proteins were transferred to a 0.2 lm cellulose nitrate membrane (Schleicher and Schuell, Dassel, Germany).…”

Section: Western Blot Analysesmentioning

confidence: 99%

“…9 Since these drug-resistant tumor cells showed cross resistance to other drugs, this phenotype was designated as altered Topo II multidrug resistance (at-MDR). 10 The decrease in Topo II activity can be caused by diminished expression levels of both Topo II isoforms 11 as well as by missense mutations within the Topo II isoenzyme encoding genes. 12 Since drug resistance is a major obstacle in successful treatment of neoplastic diseases, it is important to design alternative therapy strategies that can be utilized for the treatment of drug-resistant cancer cells.…”

mentioning

confidence: 99%

High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA topoisomerase II‐targeting drugs

Lage

Aki-Sener

Yalçın

2006

Intl Journal of Cancer

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Twenty previously synthesized fused heterocyclic DNA-topoisomerase II (Topo II)-inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities. Moreover, different multidrug-resistant variants of these cancer cell lines with decreased Topo II expression were investigated. In parental, drugsensitive cells merely the compounds BD3 and G35 showed efficacies, in terms of lM, which were similar to that of the classical Topo II inhibitor etoposide. On the other hand, most of the tested heterocyclic compounds were found more effective in drug-resistant cells than in the parental, drug-sensitive ones, and some of the compounds showed high antineoplastic efficacy in several drug-resistant cell models. Compounds BD13, BD14 and BD16 exhibited high antineoplastic activities against the drug-resistant sublines EPG85-257RNOV and EPG85-257RDB derived from gastric carcinoma, EPP85-181RNOV and EPP85-181RDB derived from pancreatic carcinoma, MCF-7/Adr derived from breast cancer, D79/ 86RNOV derived from fibrosarcoma, and MeWoETO1 derived from melanoma. Furthermore, compound D23 was found highly efficient in the multidrug-resistant variants HT-29RNOV and HT-29RDB derived from colon carcinoma, and compound D24 exhibited the highest antineoplastic activity among the tested compounds in the drug-resistant subline MDA-MB-231ROV derived from breast cancer. Key words: benzoxazole; benzimidazole; benzoxazin; DNA topisomerase II inhibitors; multidrug resistance DNA topoisomerases (Topo) 1 are enzymes that isomerise the tertiary structure of DNA without changing its primary structure. The high degree of conservation of these enzymes among prokaryotes and eukaryotes indicates an essential role in cell biology. Because its structure is a double helix, DNA is under tortional stress that results in multiplex twisting of the molecule. To be processed for replication or gene expression, the supercoiled DNA must become accessible to nucleic acids polymerases or components of the transcription machinery. This change requires relaxation and untangling of the intertwined DNA strands, which are the typical tasks of Topo.In humans, 2 classes of Topo are well characterized, type I and type II. Topo type II (Topo II) are useful as drug target, since they have an indispensable function in cell biology and they lack biological redundancy. Inhibitors of these enzymes have become central parts of both primary and adjuvant chemotherapy regimens in neoplastic diseases, and they probably will remain so for the foreseeable future. 2 Two Topo II isoforms, the 170 kDa Topo IIa and the 180 kDa Topo IIb, exist as homodimers and their amino acid sequences show homology at regions believed to be functionally significant (72% identical amino acid residues), 3 suggesting a comparable mode of action. The expression of Topo IIa varies during the cell cycle. It is low in quiescent cells, but maximal in the G 2 -M phase, whereas the expression level of Topo IIb remains constant througho...

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Modulation of DNA topoisomerase II activity and expression in melanoma cells with acquired drug resistance

Cited by 55 publications

References 15 publications

Drug-resistance in human melanoma

Drug-resistance in human melanoma

Dual inhibition of topoisomerases enhances apoptosis in melanoma cells

High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA topoisomerase II‐targeting drugs

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