Mechanisms of resistance to topoisomerase I-targeting drugs

Rasheed, Zeshaan A.; Rubin, Eric H.

doi:10.1038/sj.onc.1206935

Cited by 155 publications

(140 citation statements)

References 77 publications

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“…In this case, however, RIP3 does not seem to directly affect the choice of cell death between apoptosis and necrosis, because no significant difference of the cellular sensitivity to the other examined anticancer drugs except camptothecins was detectable (data not shown) and because RIP3-based differential responses of A cells and N cells to the Top1 inhibitors took place actually at the levels of the target protein Top1 and DNA double-strand breaks, not only at the level of cell death. In contrast, our data seem to imply that RIP3 is involved in the DNA damage [11] . The differential sensitivity of A cells and N cells to SN38 and chimmitecan also suggests that RIP3 could contribute to cellular resistance to Top1 inhibitors.…”

Section: Dear Editorcontrasting

confidence: 54%

Differential sensitivity of RIP3-proficient and deficient murine fibroblasts to camptothecin anticancer drugs

Wang

Feng

et al. 2012

Acta Pharmacol Sin

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Receptor-interacting protein 3 (RIP3) is a serine/threonine protein kinase, which has extensive substrates including its cognate kinase RIP1 and multiple metabolic enzymes involving oxidative phosphorylation [1,2] . RIP3 has been shown to be essential for development, immunity and some physiological or pathophysiological responses to exogenous and endogenous stimuli [3][4][5] . In 2009, three groups independently reported that RIP3 acted as a molecular switch between apoptosis and necrosis (also called as necroptosis) [6][7][8] . Specifically, RIP3 could turn tumor necrosis factor (TNF)-induced cell death from apoptosis to necrosis [6] . Most of small-molecule anticancer drugs elicit their anticancer effects via apoptotic induction [9] . However, it is unclear whether RIP3 affects the cellular sensitivity to small-molecule anticancer drugs.We treated A cells (NIH 3T3 cells, murine fibroblasts, RIP3 -/-; typically undergoing apoptosis in response to TNF stimulation) and N cells (NIH 3T3 cells, murine fibroblasts, RIP3 +/+ ; undergoing necroptosis in response to TNF stimulation) [6] with small-molecule anticancer drugs of different mechanisms of action. Detection by sulforhodamine B assays showed that A cells and N cells displayed differential sensitivity only to the examined topoisomerase I (Top1) inhibitors camptothecins. RIP3-deficient A cells revealed 32.6-and 40.2-fold higher sensitivity than RIP3-proficient N cells to SN38 and chimmitecan [10] , respectively ( Figure 1A). Such differential sensitivity was reflected as higher apoptosis rates ( Figure 1B) and more rapid G 2 /M arrest ( Figure 1C) in A cells than in N cells treated with chimmitecan. Consistently, exposure to chimmitecan caused faster reduction of the target protein Top1 in A cells than in N cells ( Figure 1D); and the treatment with chimmitecan or SN38 drove more γ-H2AX formation (a molecular marker for DNA double-strand breaks; Figure 1E) and produced more foci of phosphorylated ataxia telangiectasia mutated kinase (p-ATM) at Ser 1981 (sensing DNA double-strand breaks; Figures 1F and 1G) in A cells than in N cells. These results collectively indicate that the differential sensitivity of the RIP3-deficient A cells and the RIP3-proficient N cells to the examined Top1 inhibitors in all the tested events from inducing DNA double-strand breaks through sensing the damage signals to eliciting the final biological effects including cell cycle arrest, apoptosis and proliferation/growth inhibition.Both A cells and N cells were kindly gifted from Prof Jiahuai HAN, who used them to successfully demonstrate the role of RIP3 in regulating TNF-inducing cell death [6] . The differential sensitivity of the RIP3-deficient and proficient murine fibroblasts to the Top1 inhibitors suggests a role of RIP3 in determining the cellular sensitivity to those agents. In this case, however, RIP3 does not seem to directly affect the choice of cell death between apoptosis and necrosis, because no significant difference of the cellular sensitivity to the other examined anti...

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Section: Dear Editorcontrasting

confidence: 54%

Differential sensitivity of RIP3-proficient and deficient murine fibroblasts to camptothecin anticancer drugs

Wang

Feng

et al. 2012

Acta Pharmacol Sin

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“…Thus, sumoylation seems a positive regulator of camptothecin-induced formation of topo I⅐DNA complexes (23), probably by increasing the half-life of such complexes. In contrast, free topo I does not appear to be a target for sumoylation (42), because nuclease treatment is necessary to visualize ubiquitin or SUMO conjugates of topo I by Western blotting (13,19). Thus, a plausible sequence of events seems to be that camptothecin first stabilizes topo I on the DNA, which for quantitative reasons occurs more in the nucleoplasm than in the nucleolus (12), although topo I cleavage of rDNA is also stimulated by the drug (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Distinct Effects of Topoisomerase I and RNA Polymerase I Inhibitors Suggest a Dual Mechanism of Nucleolar/Nucleoplasmic Partitioning of Topoisomerase I

Christensen

Krokowski

Barthelmes

et al. 2004

Journal of Biological Chemistry

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Topoisomerase I is mostly nucleolar, because it plays a preeminent role in ribosomal DNA (rDNA) transcription. It is cleared from nucleoli following exposure to drugs stabilizing covalent DNA intermediates of the enzyme (e.g. camptothecin) or inhibiting RNA polymerases (e.g. actinomycin D), an effect summarily attributed to blockade of rDNA transcription. Here we show that two distinct mechanisms are at work: (i) Both drugs induce inactivation and segregation of the rRNA transcription machinery. With actinomycin D this leads to a co-migration of RNA-polymerase I and topoisomerase I to the nucleolar perimeter. The process has a slow onset (>20 min), is independent of topoisomerase I activity, but requires the N-terminal domain of the enzyme to colocalize with RNA polymerase I. (ii) Camptothecin induces, in addition, immobilization of active topoisomerase I on genomic DNA resulting in rapid nucleolar clearance and spreading of the enzyme to the entire nucleoplasm. This effect is independent of the state of rRNA transcription, involves segregation of topoisomerase I from RNA polymerase I, has a rapid onset (<1 min), and requires catalytic activity but neither the N-terminal domain of topoisomerase I nor its major sumoylation site. Thus, nucleolar/nucleoplasmic partitioning of topoisomerase I is regulated by interactions with RNA polymerase I and DNA but not by sumoylation.The mechanism that distributes DNA-topoisomerase I (topo I) 1 between nucleoli and nucleoplasm has been a controversial issue over a decade. Topoisomerase I catalyzes topological changes in the DNA by cutting one strand of the double helix and allowing rotation of the other (1). This mechanism releases torsion stress in DNA double helices that is created by e.g. RNA synthesis. Thus, topo I is a crucial cofactor for the transcription of nucleoplasmic genes (2) and rDNA (3, 4). The latter task seems to dominate, because topo I is concentrated in the nucleoli, and, of the three nucleolar components, it is preferentially found in the fibrillar centers, a restriction in localization that is lost when the N-terminal domain of the enzyme or parts of it are lacking (5). Topoisomerase I is thus placed in the vicinity of rDNA, RNA polymerase I, and rDNA transcription, which are also restricted to the fibrillar centers of the nucleolus (6). Nucleolar positioning of topo I is highly susceptible to exogenous perturbation. The enzyme is lost from fibrillar centers, when cells are cultured at an inappropriate temperature (5). It is also lost from nucleoli in response to camptothecin and related compounds that inhibit the religation step of the DNA cleavage-religation mechanism and thus stabilize the enzyme in covalent DNA intermediates (7,8). Because such compounds also inhibit RNA synthesis (9) and because direct inhibitors of RNA polymerase I such as actinomycin D (10) also remove topo I from the nucleoli, it has been proposed that the same cellular mechanism (i.e. loss of rRNA synthesis) is responsible for nucleolar clearance of topo I in response to both typ...

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“…As with other clinically effective agents, the clinical resistance to camptothecins may be a multifactorial phenomenon likely involving cellular, pharmacological and tumor-specific factors [18,19]. On the basis of the peculiar features of the camptothecin structure (i.e., opening of the lactone ring) and of the mechanism of action (i.e., conversion of the single-strand breaks in irreversible double-strand breaks during S-phase), prolonged drug exposure is a critical requisite to overcome the shortcoming related to reversibility of the cleavable complex.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

Zuco¹,

Supino²,

Favini³

et al. 2010

Biochemical Pharmacology

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ST1968 (namitecan), a novel 7-modified hydrophilic camptothecin, was found to be effective against tumor models relatively resistant to topotecan and irinotecan. Based on this observation, this study was designed to investigate the cellular and antitumor effects of ST1968 in a subline of A431, squamous cell carcinoma, selected for resistance to topotecan (A431/TPT). This model was characterized by a slow growth rate, associated with down-regulation of EGFR and topoisomerase I. In contrast to other camptothecins (SN38 and gimatecan), ST1968 was able to overcome almost completely the resistance at cellular level. The cellular pharmacokinetics indicated a comparable accumulation and retention of ST1968 in sensitive and resistant cells, in spite of expression of the efflux transporter, P-glycoprotein, in resistant cells. The uptake and retention of topotecan was dramatically reduced in both tumor cell lines, but more evident in the resistant one. In contrast to topotecan, ST1968 retained an outstanding efficacy in vivo against the resistant tumor (A431/TPT). The results are consistent with the interpretation that ST1968 was able to overcome the most relevant mechanisms associated with the development of topotecan resistance (i.e., slow proliferation and target downregulation) owing to its peculiar pharmacokinetic behaviour.

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Mechanisms of resistance to topoisomerase I-targeting drugs

Cited by 155 publications

References 77 publications

Differential sensitivity of RIP3-proficient and deficient murine fibroblasts to camptothecin anticancer drugs

Differential sensitivity of RIP3-proficient and deficient murine fibroblasts to camptothecin anticancer drugs

Distinct Effects of Topoisomerase I and RNA Polymerase I Inhibitors Suggest a Dual Mechanism of Nucleolar/Nucleoplasmic Partitioning of Topoisomerase I

Efficacy of ST1968 (namitecan) on a topotecan-resistant squamous cell carcinoma

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