Altered DNA topoisomerase II in multidrug resistance

Beck, William T.; Danks, Mary K.; Wolverton, Judith S.; Granzen, Bernd; Chen, Mei; Schmidt, Carla Adriana Pizarro; Bugg, Barbara Y.; Friche, Ellen; Suttle, D P

doi:10.1007/bf00749000

Cited by 19 publications

(7 citation statements)

References 17 publications

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“…This drug-resistance phenomenon has been termed atypical multidrug resistance to differentiate it from MDR1-mediated multidrug resistance (120). VP-16, mitoxantrone, or m-AMSA) often leads to cross-resistance to all other TOP2 poisons (40, 120).…”

Section: Multiple Mechanisms Of Topoisomerase II Inhibitionmentioning

confidence: 99%

Tumor Cell Death Induced by Topoisomerase-Targeting Drugs

Liu

2001

Annu. Rev. Pharmacol. Toxicol.

498

442

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DNA topoisomerases are double-edged swords. They are essential for many vital functions of DNA during normal cell growth. However, they are also highly vulnerable under various physiological and nonphysiological stresses because of their delicate act on breaking and rejoining DNA. These stresses (e.g. exposure to topoisomerase poisons, acidic pH, and oxidative stresses) can convert DNA topoisomerases into DNA-breaking nucleases, resulting in cell death and/or genomic instability. The importance of topoisomerase-mediated DNA cleavage in tumor cell death and carcinogenesis has been recognized. This review focuses on recent findings concerning the molecular mechanisms of the stress responses to topoisomerase-mediated DNA damage. The involvement of ubiquitin/26S proteasome and SUMO/UBC9 in these processes, as well as the role of topoisomerase cleavable complexes in apoptotic cell death are discussed.

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Section: Multiple Mechanisms Of Topoisomerase II Inhibitionmentioning

confidence: 99%

Tumor Cell Death Induced by Topoisomerase-Targeting Drugs

Liu

2001

Annu. Rev. Pharmacol. Toxicol.

498

442

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“…One of the mechanisms found to contribute to drug resistance is mediated by decreased activity of Topo-II. 18 Only a few studies have investigated the relevance of Topo-II regarding drug resistance in melanoma. An increase of topoisomerase activity in association with resistance to doxorubicin and etoposide in melanoma cells has been reported.…”

Section: Drug Resistance Mediated By Altered Enzyme Activationmentioning

confidence: 99%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

165

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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“…However, multidrug resistance (MDR) continues to be a major obstacle for successful anticancer therapy. Resistance can occur by many mechanisms, including mutation of the drug target [1,2], inactivation of the drug [3], cellular redistribution of the drug [4], activation of DNA repair mechanisms [5], inhibition of apoptosis [5], and efflux of the drug from the cells [6][7][8]. One of the most widespread and best understood mechanisms of resistance to chemotherapy involves expression of P-glycoprotein (P-gp) [9].…”

Section: Introductionmentioning

confidence: 99%

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

et al. 2007

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The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.

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Altered DNA topoisomerase II in multidrug resistance

Cited by 19 publications

References 17 publications

Tumor Cell Death Induced by Topoisomerase-Targeting Drugs

Tumor Cell Death Induced by Topoisomerase-Targeting Drugs

Drug-resistance in human melanoma

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

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