DNA topoisomerase II mutations and resistance to anti‐tumor drugs

Vassetzky, Yegor S.; Alghisi, Gian-Carlo; Gasser, Susan M.

doi:10.1002/bies.950170906

Cited by 70 publications

(36 citation statements)

References 54 publications

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“…[37][38][39] This is also the case with BTZ resistance; we and others have reported mutations in the b5 subunit in pre-clinical BTZ-resistant cell line models. 20,21,34,40 In this study, we identified four novel mutations, all residing within the BTZbinding pocket, and cluster with the previously reported G322A (Ala49Thr) 20,21,40 and C323T (Ala49Val) 34 mutations.…”

Section: Discussionmentioning

confidence: 99%

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

et al. 2011

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Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the b5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZresistant cells revealed upregulation of mutant b5 subunit of the proteasome. These newly identified b5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the b5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant b5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the a7 subunit of the proteasome can overcome this drug resistance modality.

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Section: Discussionmentioning

confidence: 99%

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

et al. 2011

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“…We now believe that this is incorrect. All available evidence indicates that non-covalent topoisomerase II poisons act within the active site of the enzyme at the interface between the protein and DNA substrate [15,16,[133][134][135][136][137]. Furthermore, mechanistic studies suggest that it is actually the interactions between topoisomerase II and these compounds that serve as the point of entry into the enzyme-DNA complex [135][136][137][138].…”

Section: Non-covalent Topoisomerase II Poisonsmentioning

confidence: 99%

“…Although topoisomerase II-targeted anticancer drugs act at the enzyme-DNA interface [15,16,104,[133][134][135][136][137], the accumulation of drugs in the double helix has the potential to inhibit enzyme binding or activity. Because the generation of positive superhelical twists by DNA intercalation induces torsional stress in the double helix [130,189], the ability of these molecules to absorb intercalative compounds is limited.…”

Section: Effects Of Dna Supercoiling On Topoisomerase Ii-mediated Dnamentioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

365

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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“…[20][21][22][23][24][25] In addition, in some particular cell lines, topoisomerase II gene mutations have been identified and suggested to be responsible for the reduced drug sensitivity to DNA topoisomerase inhibitors. [26][27][28][29] Conversely, more recent studies have shown that increasing the intracellular level of the enzyme by transfection of topoisomerase genes can restore the sensitivity of resistant cancer cell lines to DNA topoisomerase inhibitors. [30][31][32][33][34] On the other hand, anthracyclines are wellknown chemotherapeutic agents that can cause cardiotoxicity in clinical use.…”

Section: Introductionmentioning

confidence: 99%

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

et al. 2003

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Topoisomerase genes were analyzed at both DNA and RNA levels in 25 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The results of molecular analysis were compared to risk group classification of children in order to identify molecular characteristics associated with response to therapy. At diagnosis, allelic imbalance at topoisomerase IIa (TOP2A) gene locus was found in 75% of informative cases whereas topoisomerase I and IIb gene loci are altered in none or only one case, respectively. By semiquantitative Polymerase chain reaction, we found a 2.5 to 8-fold TOP2A gene amplification in 72% of the children, which was correlated to gene overexpression in every case. These results show that TOP2A gene amplification is a frequent event in ALL at diagnosis. Interestingly, we also identified a small population of children that do not present TOP2A gene amplification or gene overexpression and who are significantly associated with very high risk classified patients showing glucocorticoid resistance. In conclusion, characterization of TOP2A gene status in childhood ALL at diagnosis provides useful complementary information for risk assessment.

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DNA topoisomerase II mutations and resistance to anti‐tumor drugs

Cited by 70 publications

References 54 publications

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

DNA topoisomerase II, genotoxicity, and cancer

Modification of topoisomerase genes copy number in newly diagnosed childhood acute lymphoblastic leukemia

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