Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage

Zeng, Xing; Sigoillot, Frederic; Gaur, Shantanu; Choi, Sung‐Woon; Pfaff, Kathleen L.; Oh, Dong Chan; Hathaway, Nathaniel A.; Dimova, Nevena; Cuny, Gregory D.; King, Randall W.

doi:10.1016/j.ccr.2010.08.010

Cited by 295 publications

(371 citation statements)

References 46 publications

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“…Although these data indicate that APC/C regulates centrosome clustering and the formation of bipolar spindle in CA cells, the actual 'effector' protein, which is regulated by APC/C, remained unknown. We observed that the spindle morphology induced by APC/C knockdown or treatment with the APC/C-CDC20/CDH1 inhibitor proTAME 11,12 showed a well-structured threefold or fourfold rotational symmetry and the spindle poles clearly located at the periphery of the DNA (Figs 1d and 2a; and Supplementary Fig. 3a).…”

Section: Resultsmentioning

confidence: 84%

“…The major role of APC/C-CDC20 is to initiate transition from metaphase to anaphase via targeting for degradation several mitotic proteins, such as cyclin B and Securin. Genetic ablation, knockdown or inhibition of CDC20 results in metaphase arrest and cell death that is associated with stabilization of APC/C-CDC20 substrates 11,12,37 . In addition, genetic ablation of CDC20 results in complete tumour regression in mice in comparison with treatment with taxol, vincristine or BI2536, which only induces partial responses 37 .…”

Section: Ub-eg5mentioning

confidence: 99%

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APC/C is an essential regulator of centrosome clustering

et al. 2014

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Section: Resultsmentioning

confidence: 84%

Section: Ub-eg5mentioning

confidence: 99%

APC/C is an essential regulator of centrosome clustering

et al. 2014

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“…These results have been reinforced with the discovery of tosyl-L-arginine methyl ester (TAME), an APC/C small-molecule inhibitor that efficiently arrests tumor cells in mitosis triggering cell death. 73 Although targeting mitotic exit may be highly efficient, how can this strategy discriminate between tumor and normal proliferating cells? As previously suggested, APC/C-Cdc20 inhibitors could be useful in combination with other mitotic poisons by slowing cyclin B1 degradation and thus providing enough time to reach the apoptotic threshold of tumor cells.…”

Section: Cell Deathmentioning

confidence: 99%

Killing cells by targeting mitosis

2012

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Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis.As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.

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“…27 For these reasons, to block mitotic exit, we opted for the pharmacological inhibition of the APC/C with a previously characterized inhibitor, proTAME. 40 Since manipulation of mitotic block seems to be a promising approach to kill cancerous cells, in this paper we attempted to answer the questions: What is the best strategy to induce mitotic death, by extending the mitotic block or by enhancing mitotic exit? Which one would synergize best with antimitotic drugs?…”

Section: Introductionmentioning

confidence: 99%

Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy

et al. 2013

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Microtubule-poisoning drugs, such as Paclitaxel (or taxol, PtX), are powerful and commonly used anti-neoplastic agents for the treatment of several malignancies. PtX triggers cell death, mainly through a mitotic arrest following the activation of the spindle assembly checkpoint (SAC). Cells treated with PtX slowly slip from this mitotic block and die by mitotic catastrophe. However, cancer cells can acquire or are intrinsically resistant to this drug, posing one of the main obstacles for PtX clinical effectiveness. In order to override PtX resistance and increase its efficacy, we investigated both the enhancement of mitotic slippage and the block of mitotic exit.to test these opposing strategies, we used physiological hyperthermia (Ht) to force exit from PtX-induced mitotic block and the anaphase-promoting complex/cyclosome (APC/C) inhibitor, protAMe, to block mitotic exit. We observed that application of Ht on PtX-treated cells forced mitotic slippage, as shown by the rapid decline of cyclin B levels and by microscopy analysis. Similarly, Ht induced mitotic exit in cells blocked in mitosis by other antimitotic drugs, such as Nocodazole and the Aurora A inhibitor MLN8054, indicating a common effect of Ht on mitotic cells. On the other hand, protAMe prevented mitotic exit of PtX and MLN8054 arrested cells, prolonged mitosis, and induced apoptosis. In addition, we showed that protAMe prevented Ht-mediated mitotic exit, indicating that stress-induced APC/C activation is necessary for Ht-induced mitotic slippage.Finally, Ht significantly increased PtX cytotoxicity, regardless of cancer cells' sensitivity to PtX, and this activity was superior to the combination of PtX with pro-tAMe. Our data suggested that forced mitotic exit of cells arrested in mitosis by anti-mitotic drugs, such as PtX, can be a more successful anticancer strategy than blocking mitotic exit by inactivation of the APC/C.

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Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage

Cited by 295 publications

References 46 publications

APC/C is an essential regulator of centrosome clustering

APC/C is an essential regulator of centrosome clustering

Killing cells by targeting mitosis

Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy

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